N-acylsulfonamide apoptosis promoters

ABSTRACT

N-Benzoyl arylsulfonamides having the formula:                    
     are BCL-X1 inhibitors and are useful for promoting apoptosis. Also disclosed are BCL-X1 inhibiting compositions and methods of promoting apoptosis in a mammal.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Patent ApplicationSer. No. 60/233,866, filed Sep. 20, 2000, which is hereby incorporatedby reference.

TECHNICAL FIELD

The present invention relates to substituted N-acylsulfonamides whichare useful for promoting apoptosis, methods of making the compounds,compositions containing the compounds, and methods of treatment usingthe compounds.

BACKGROUND OF THE INVENTION

Apoptosis is a mode of cell death in which the cell commits suicideeither to ensure proper development of the organism or to destroy cellsthat represent a threat to the organism's integrity. Morphologically,apoptosis is characterized by blebbing of the plasma membrane, shrinkingof the cytoplasm and nucleus, and fragmenting into particles which areengulfed by phagocytic cells. Although apoptosis plays a critical rolein normal development, its impairment is thought to be a significantfactor in the etiology of such diseases as cancer, autoimmune disorders,inflammatory diseases, and viral infections. Conversely, increasedapoptosis has been linked to AIDS and neurodegenerative diseases such asParkinson's disease, stroke, and Alzheimer's disease.

BCL-X1 is a protein which, in healthy cells, is expressed in the outermembranes of the mitochondria, the endoplasmic reticulum, and thenuclear envelope. Its function is to bind to specific protein/proteasecomplexes and prevent cell apoptosis. Upon internal damage to the cellthe protein/protease complexes are released, and cause the process ofapoptosis to begin. An over-expression of BCL-X1, often present incancerous and other diseased cells, results in the blocking of apoptoticsignals and allows the cells to proliferate (Cancer 1999, 85, 164-170;and references cited therein). It is believed that by blocking BCL-X1,apoptosis can be induced in diseased cells, and can provide an effectivetherapy for cancer and other diseases caused by the impairment of theapoptotic process. Based on these findings and the absence of BCL-X1inhibitors from current cancer therapies, there is a continuing need forcompounds which can trigger apoptosis through the inhibition of the BCLfamily of proteins.

SUMMARY OF THE INVENTION

In its principle embodiment the present invention provides a compound offormula (I):

or a therapeutically acceptable salt thereof wherein

A is selected from the group consisting of phenyl and a five- orsix-membered aromatic carbocyclic ring wherein from one to three carbonatoms are replaced by a heteroatom selected from the group consisting ofnitrogen, oxygen, and sulfur, and wherein A is substituted throughcarbon atoms in the ring;

R¹ is selected from the group consisting of alkyl, haloalkyl, nitro, and—NR⁵R⁶;

R², and R³ are independently selected from the group consisting ofhydrogen, alkenyl, alkoxy, alkyl, alkylsulfanyl, alkynyl, aryl,arylalkoxy, aryloxy, aryloxyalkoxy, arylsulfanyl, arylsulfanylalkoxy,carbonyloxy, cycloalkylalkoxy, cycloalkyloxy, halo, haloalkoxy,haloalkyl, heterocycle, (heterocycle)oxy, hydroxy, nitro, and —N⁵R⁶,

R⁴ is selected from the group consisting of aryl, arylalkenyl,arylalkoxy, cycloalkenyl, cycloalkyl, halo, heterocycle, and(heterocycle)alkoxy;

R⁵ and R⁶ are independently selected from the group consisting ofhydrogen, alkenyl, alkoxyalkyl, alkoxycarbonylalkyl, alkyl,alkylsulfanylalkyl, alkylsulfonylalkyl, aryl, arylalkyl,arylalkylsulfanylalkyl, aryloxyalkyl, arylsulfanylalkyl,arylsulfinylalkyl, arylsulfonylalkyl, carboxyalkyl, cycloalkenyl,cycloalkenylalkyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkylcarbonyl,heterocycle, (heterocycle)alkyl, (heterocycle)sulfanylalkyl,hydroxyalkyl, a nitrogen protecting group, and —N═CR⁷R⁸; or

R⁵ and R⁶, together with the nitrogen atom to which they are attached,form a ring selected from the group consisting of imidazolyl,morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, pyrrolyl,thiomorpholinyl, and thiomorpholinyl dioxide; and

R⁷ and R⁸ are alkyl, or

R⁷ and R⁸, together with the carbon atom to which they are attached,form an aryl group; and

R¹⁵ is selected from the group consisting of hydrogen, alkyl, and halo.

In another embodiment the present invention provides a compound offormula (I) wherein A is selected from the group consisting of phenyl,pyridinyl, and furyl; and R¹-R⁸ and R¹⁵ are as previously defined.

In another embodiment the present invention provides a compound offormula (I) wherein A is selected from the group consisting of phenyl,pyridinyl, and furyl; R³ is selected from the group consisting ofhydrogen, alkenyl, aryl, and heterocycle; and R¹, R², R⁴⁻⁸, and R¹⁵ areas previously defined.

In another embodiment the present invention provides a compound offormula (I) wherein A is selected from the group consisting of phenyl,pyridinyl, and furyl; R³ is selected from the group consisting ofhydrogen, alkenyl, aryl, and heterocycle; R² is selected from the groupconsisting of arylsulfanylalkoxy, cycloalkylalkoxy, and cycloalkyloxy;and R¹, R⁴, and R¹⁵ are as previously defined.

In another embodiment the present invention provides a compound offormula (I) wherein A is selected from the group consisting of phenyl,pyridinyl, and furyl; R³ is selected from the group consisting ofhydrogen, alkenyl, aryl, and heterocycle; R² is —NR⁵R⁶; and R¹, R⁴, R⁷,R⁸, and R¹⁵ are as previously defined.

In another embodiment the present invention provides a compound offormula (I) wherein A is selected from the group consisting of phenyl,pyridinyl, and furyl; R³ is selected from the group consisting ofhydrogen, alkenyl, aryl, and heterocycle; R² is —NR⁵R⁶; one of R⁵ and R⁶is selected from the group consisting of alkyl, aryl, arylalkyl,arylalkylsulfanylalkyl, arylsulfinylalkyl, arylsulfonylalkyl,cycloalkylcarbonyl, heterocycle, (heterocycle)alkyl,heterocyclesulfanylalkyl, and —N═CR⁷R⁸; and the other is hydrogen; andR¹, R⁴, R⁷, R⁸, and R¹⁵ are as previously defined.

In another embodiment the present invention provides a compound offormula (I) wherein A is selected from the group consisting of phenyl,pyridinyl, and furyl; R³ is selected from the group consisting ofhydrogen, alkenyl, aryl, and heterocycle; R² is —NR⁵R⁶; one of R⁵ and R⁶is (cycloalkyl)alkyl and the other is arylsulfanylalkyl; and R¹, R⁴, andR¹⁵ are as previously defined.

In another embodiment the present invention provides a compound offormula (I) wherein A is selected from the group consisting of phenyl,pyridinyl, and furyl; R³ is selected from the group consisting ofhydrogen, alkenyl, aryl, and heterocycle; R² is —NR⁵R⁶; one of R⁵ and R⁶is cycloalkyl and the other is hydrogen; and R¹, R⁴ and R¹⁵ are aspreviously defined.

In another embodiment the present invention provides a compound offormula (I) wherein A is selected from the group consisting of phenyl,pyridinyl, and furyl; R³ is selected from the group consisting ofhydrogen, alkenyl, aryl, and heterocycle; R² is —NR⁵R⁶; one of R⁵ and R⁶is (cycloalkyl)alkyl and the other is hydrogen; and R¹, R⁴, and R⁵ areas previously defined.

In another embodiment the present invention provides a compound offormula (I) wherein A is selected from the group consisting of phenyl,pyridinyl, and furyl; R³ is selected from the group consisting ofhydrogen, alkenyl, aryl, and heterocycle; R² is —NR⁵R⁶; one of R⁵ and R⁶is arylsulfanylalkyl and the other is hydrogen; and R¹, R⁴, and R¹⁵ areas previously defined.

In another embodiment the present invention provides a compound offormula (I) wherein A is selected from the group consisting of phenyl,pyridinyl, and furyl; R³ is selected from the group consisting ofhydrogen, alkenyl, aryl, and heterocycle; R² is —NR⁵R⁶; one of R⁵ and R⁶is arylalkylsulfanyl and the other is hydrogen; R⁴ is selected from thegroup consisting of arylalkenyl, arylalkoxy, cycloalkenyl, cycloalkyl,and (heterocycle)alkoxy; and R¹ and R¹⁵ are as previously defined.

In another embodiment the present invention provides a compound offormula (I) wherein A is selected from the group consisting of phenyl,pyridinyl, and furyl; R³ is selected from the group consisting ofhydrogen, alkenyl, aryl, and heterocycle; R² is —NR⁵R⁶; one of R⁵ and R⁶is arylsulfanylalkyl and the other is hydrogen; R⁴ is aryl; and R¹ andR¹⁵ are as previously defined.

In another embodiment the present invention provides a compound offormula (I) wherein A is selected from the group consisting of phenyl,pyridinyl, and furyl; R³ is selected from the group consisting ofhydrogen, alkenyl, aryl, and heterocycle; R² is —NR⁵R⁶; one of R⁵ and R⁶is arylsulfanylalkyl and the other is hydrogen; R⁴ is aryl wherein thearyl is unsubstituted or has one substituent; and R¹ and R¹⁵ are aspreviously defined.

In another embodiment the present invention provides a compound offormula (I) wherein A is selected from the group consisting of phenyl,pyridinyl, and furyl; R³ is selected from the group consisting ofhydrogen, alkenyl, aryl, and heterocycle; R² is —NR⁵R⁶; one of R⁵ and R⁶is arylsulfanylalkyl and the other is hydrogen; R⁴ is aryl wherein thearyl has two substituents; and R¹ and R¹⁵ are as previously defined.

In another embodiment the present invention provides a compound offormula (I) wherein A is selected from the group consisting of phenyl,pyridinyl, and furyl; R³ is selected from the group consisting ofhydrogen, alkenyl, aryl, and heterocycle; R² is —NR⁵R⁶; one of R⁵ and R⁶is arylsulfanylalkyl and the other is hydrogen; R⁴ is heterocycle; andR¹ and R¹⁵ are as previously defined.

In another embodiment the present invention provides a compound offormula (I) wherein A is selected from the group consisting of phenyl,pyridinyl, and furyl; R³ is selected from the group consisting ofhydrogen, alkenyl, aryl, and heterocycle; R² is —NR⁵R⁶; one of R⁵ and R⁶is arylsulfanylalkyl and the other is hydrogen; R⁴ is heterocyclewherein the heterocycle is unsubstitued or has one substituent; and R¹and R¹⁵ are as previously defined.

In another embodiment the present invention provides a compound offormula (I) wherein A is selected from the group consisting of phenyl,pyridinyl, and furyl; R³ is selected from the group consisting ofhydrogen, alkenyl, aryl, and heterocycle; R² is —NR⁵R⁶; one of R⁵ and R⁶is arylsulfanylalkyl and the other is hydrogen; R⁴ is heterocyclewherein the heterocycle has two or three substituents; and R¹ and R¹⁵are as previously defined.

In another embodiment, the present invention provides a pharmaceuticalcomposition comprising a compound of formula (I), or a therapeuticallyacceptable salt thereof, in combination with a therapeuticallyacceptable carrier.

In another embodiment, the present invention provides a method ofpromoting apoptosis in a mammal in recognized need thereof comprisingadministering to the mammal a therapeutically acceptable amount of acompound of formula (I) or a therapeutically acceptable salt thereof.

DETAILED DESCRIPTION OF THE INVENTION

Compounds of the present invention comprise substituted N-benzoylarylsulfonamides which are useful for the treatment ofapoptosis-mediated diseases.

As used in the present specification the following terms have themeanings indicated.

The term “alkanoyl,” as used herein, represents an alkyl group attachedto the parent molecular moiety through a carbonyl group. The alkanoylgroups of this invention can be optionally substituted with one or twogroups independently selected from the group consisting of hydroxy and—NR⁵R⁶, wherein R⁵ and R⁶ are as previously defined.

The term “alkanoylalkyl,” as used herein, represents an alkanoyl groupattached to the parent molecular moiety through an alkyl group.

The term “alkenyl,” as used herein, represents a straight or branchedchain group of one to twelve carbon atoms derived from a straight orbranched chain hydrocarbon containing at least one carbon-carbon doublebond.

The term “alkoxy,” as used herein, represents an alkyl group attached tothe parent molecular moiety through an oxygen atom.

The term “alkoxyalkanoyl,” as used herein, represents an alkoxy groupattached to the parent molecular moiety through an alkanoyl group.

The term “alkoxyalkoxy,” as used herein, represents an alkoxy groupattached to the parent molecular moiety through another alkoxy group.

The term “alkoxyalkoxyalkyl,” as used herein, represents an alkoxyalkoxygroup attached to the parent molecular moiety through an alkyl group.

The term “alkoxyalkoxycarbonyl,” as used herein, represents analkoxyalkoxy group attached to the parent molecular moiety through acarbonyl group.

The term “alkoxyalkyl,” as used herein, represents an alkoxy groupattached to the parent molecular moiety through an alkyl group.

The term “alkoxycarbonyl,” as used herein, represents an alkoxy groupattached to the parent molecular moiety through a carbonyl group.

The term “alkoxycarbonylalkyl,” as used herein, represents analkoxycarbonyl group attached to the parent molecular moiety through analkyl group.

The term “alkyl,” as used herein, represents a group of one to twelvecarbon atoms derived from a straight or branched chain saturatedhydrocarbon.

The term “alkylamino,” as used herein, represents —N(R¹⁴)₂, wherein R¹⁴is alkyl.

The term “alkylaminoalkyl,” as used herein, represents an alkylaminogroup attached to the parent molecular moiety through an alkyl group.

The term “alkylaminocarbonyl,” as used herein, represents an alkylaminogroup attached to the parent molecular moiety through a carbonyl group.

The term “alkylaminocarbonylalkyl,” as used herein, represents analkylaminocarbonyl group attached to the parent molecular moiety throughan alkyl group.

The term “alkylidene,” as used herein, represents an alkyl groupattached to the parent molecular moiety through a carbon-carbon doublebond.

The term “alkylsulfanyl,” as used herein, represents an alkyl groupattached to the parent molecular moiety through a sulfur atom.

The term “alkylsulfanylalkyl,” as used herein, represents analkylsulfanyl group attached to the parent molecular moiety through analkyl group.

The term “alkylsulfonyl,” as used herein, represents an alkyl groupattached to the parent molecular moiety through a sulfonyl group.

The term “alkylsulfonylalkyl,” as used herein, represents analkylsulfonyl group attached to the parent molecular moiety through analkyl group.

The term “alkynyl,” as used herein, represents a straight or branchedchain group of one to twelve carbon atoms containing at least onecarbon-carbon triple bond.

The term “amino,” as used herein, represents —NR⁹R¹⁰, wherein R⁹ and R¹⁰are independently selected from the group consisting of hydrogen,alkanoyl, alkenyl, alkoxyalkyl, alkoxyalkoxyalkyl, alkoxycarbonyl,alkyl, alkylaminoalkyl, alkylaminocarbonylalkyl, aryl, arylalkyl,cycloalkyl, (cycloalkyl)alkyl, cycloalkylcarbonyl, haloalkanoyl,haloalkyl, (heterocycle)alkyl, heterocyclecarbonyl, hydroxyalkyl, anitrogen protecting group, —C(NH)NH₂, and —C(O)NR⁵R⁶, wherein R⁵ and R⁶are as previously defined; wherein the aryl; the aryl part of thearylalkyl; the cycloalkyl; the cycloalkyl part of the (cycloalkyl)alkyland the cycloalkylcarbonyl; and the heterocycle part of the(heterocycle)alkyl and the heterocyclecarbonyl can be optionallysubstituted with one, two, three, four, or five substituentsindependently selected from the group consisting of alkanoyl, alkoxy,alkyl, cyano, halo, haloalkoxy, haloalkyl, hydroxy, and nitro.

The term “aminoalkanoyl,” as used herein, represents an amino groupattached to the parent molecular moiety through an alkanoyl group.

The term “aminoalkyl,” as used herein, represents an amino groupattached to the parent molecular moiety through an alkyl group.

The term “aminocarbonyl,” as used herein, represents an amino groupattached to the parent molecular moiety through a carbonyl group.

The term “aminocarbonylalkyl,” as used herein, represents anaminocarbonyl group attached to the parent molecular moiety through analkyl group.

The term “aminosulfonyl,” as used herein, represents an amino groupattached to the parent molecular moiety through a sulfonyl group.

The term “aryl,” as used herein, represents a phenyl group or a bicyclicor tricyclic fused ring system wherein one or more of the fused rings isa phenyl group. Bicyclic fused ring systems are exemplified by a phenylgroup fused to a cycloalkyl group as defined herein, a cycloalkenylgroup as defined herein, or another phenyl group. Tricyclic fused ringsystems are exemplified by a bicyclic fused ring system fused to acycloalkyl group as defined herein, a cycloalkenyl group as definedherein, or another phenyl group. Representative examples of arylinclude, but are not limited to, anthracenyl, azulenyl, fluorenyl,indanyl, indenyl, naphthyl, phenyl, and tetrahydronaphthyl. Aryl groupshaving an unsaturated or partially saturated ring fused to an aromaticring can be attached through the saturated or the unsaturated part ofthe group. The aryl groups of this invention can be optionallysubstituted with one, two, three, four, or five substituentsindependently selected from the group consisting of alkanoyl, alkenyl,alkoxy, alkoxyalkanoyl, alkoxyalkyl, alkoxycarbonyl,alkoxycarbonylalkyl, alkyl, alkynyl, amino, aminoalkyl, aminocarbonyl,aminocarbonylalkyl, aminosulfonyl, aryl, aryloxy, arylsulfanyl,carbonyloxy, cyano, halo, haloalkoxy, haloalkyl, heterocycle,(heterocycle)alkyl, heterocyclecarbonylalkenyl,heterocyclecarbonylalkyl, hydroxy, hydroxyalkyl, nitro, oxo, and—C(NH)NH₂, wherein the aryl; the aryl part of the aryloxy and thearylsulfanyl; the heterocycle; and the heterocycle part of the(heterocycle)alkyl, the heterocyclecarbonylalkenyl, and theheterocyclecarbonylalkyl can be further optionally substituted with one,two, or three substituents independently selected from the groupconsisting of alkoxyalkanoyl, alkoxycarbonyl, alkyl, alkylsulfonyl,aminocarbonyl, aminosulfonyl, cyano, halo, haloalkoxy, haloalkyl,hydroxy, nitro, oxo, and —C(NH)NH₂. In addition, the heterocycle and theheterocycle part of the (heterocycle)alkyl, theheterocyclecarbonylalkenyl, and the heterocyclecarbonylalkyl can befurther optionally substituted with an additional aryl group, whereinthe aryl can be optionally substituted with one, two, or threesubstituents independently selected from the group consisting of alkoxy,alkyl, cyano, halo, hydroxy, and nitro.

The term “arylalkenyl,” as used herein, represents an aryl groupattached to the parent molecular moiety through an alkenyl group.

The term “arylalkoxy,” as used herein, represents an aryl group attachedto the parent molecular moiety through an alkoxy group.

The term “arylalkoxyalkanoyl,” as used herein, represents an arylalkoxygroup attached to the parent molecular moiety through an alkanoyl group.

The term “arylalkoxycarbonyl,” as used herein, represents an arylalkoxygroup attached to the parent molecular moiety through a carbonyl group.

The term “arylalkyl,” as used herein, represents an alkyl groupsubstituted with at least one aryl group. The alkyl part of thearylalkyl can be optionally substituted with one or two amino groups.

The term “arylalkylsulfanyl,” as used herein, represents an arylalkylgroup attached to the parent molecular moiety through a sulfur atom.

The term “arylalkylsulfanylalkyl,” as used herein, represents anarylalkylsulfanyl group attached to the parent molecular moiety throughan alkyl group.

The term “arylalkylsulfonyl,” as used herein, represents an arylalkylgroup attached to the parent molecular moiety through a sulfonyl group.

The term “arylcarbonyl,” as used herein, represents an aryl groupattached to the parent molecular moiety through a carbonyl group.

The term “aryloxy,” as used herein, represents an aryl group attached tothe parent molecular moiety through an oxygen atom.

The term “aryloxyalkoxy,” as used herein, represents an aryloxy groupattached to the parent molecular moiety through an alkoxy group.

The term “aryloxyalkyl,” as used herein, represents an aryloxy groupattached to the parent molecular moiety through an alkyl group.

The term “arylsulfanyl,” as used herein, represents an aryl groupattached to the parent molecular moiety through a sulfur atom.

The term “arylsulfanylalkoxy,” as used herein, represents anarylsulfanyl group attached to the parent molecular moiety through analkoxy group.

The term “arylsulfanylalkyl,” as used herein, represents an arylsulfanylgroup attached to the parent molecular moiety through an alkyl group.The alkyl part of the arylsulfanylalkyl can be optionally substitutedwith one or two substituents independently selected from the groupconsisting of alkoxy, alkoxycarbonyl, amino, aminocarbonyl, arylalkoxy,azido, carboxy, cycloalkyl, halo, heterocycle, (heterocycle)alkoxy,(heterocycle)carbonyl, and hydroxy.

The term “arylsulfinyl,” as used herein, represents an aryl groupattached to the parent molecular moiety through a sulfinyl group.

The term “arylsulfinylalkyl,” as used herein, represents an arylsulfinylgroup attached to the parent molecular moiety through an alkyl group.The alkyl part of the arylsulfinylalkyl can be optionally substitutedwith one or two amino groups.

The term “arylsulfonyl,” as used herein, represents an aryl groupattached to the parent molecular moiety through a sulfonyl group.

The term “arylsulfonylalkyl,” as used herein, represents an arylsulfonylgroup attached to the parent molecular moiety through an alkyl group.The alkyl part of the arylsulfonylalkyl can be optionally substitutedwith one or two amino groups.

The term “azido,” as used herein, represents —N₃.

The term “carbonyl,” as used herein, represents —C(O)—.

The term “carbonyloxy,” as used herein, represents an alkanoyl groupattached to the parent molecular moiety through an oxygen atom.

The term “carboxy,” as used herein, represents —CO₂H.

The term “carboxyalkyl,” as used herein, represents a carboxy groupattached to the parent molecular moiety through an alkyl group.

The term “cyano,” as used herein, represents —CN.

The term “cyanoalkyl,” as used herein, represents a cyano group attachedto the parent molecular moiety through an alkyl group.

The term “cycloalkenyl,” as used herein, represents a non-aromatic ringsystem having three to ten carbon atoms and one to three rings, whereineach five-membered ring has one double bond, each six-membered ring hasone or two double bonds, each seven- and eight-membered ring has one tothree double bonds, and each nine-to ten-membered ring has one to fourdouble bonds. Examples of cycloalkenyl groups include cyclohexenyl,octahydronaphthalenyl, norbornylenyl, and the like. The cycloalkenylgroups of this invention can be optionally substituted with one, two,three, four, or five substituents independently selected from the groupconsisting of alkoxy, alkoxycarbonyl, alkyl, aminoalkyl, arylalkoxy,aryloxy, arylsulfanyl, halo, haloalkoxy, haloalkyl, and hydroxy, whereinthe aryl part of the arylalkoxy, the aryloxy, and the arylsulfanyl canbe further optionally substituted with one, two, or three substituentsindependently selected from the group consisting of alkoxy, alkyl, halo,haloalkoxy, haloalkyl, and hydroxy.

The term “cycloalkenylalkyl,” as used herein, represents a cycloalkenylgroup attached to the parent molecular moiety through an alkyl group.

The term “cycloalkyl,” as used herein, represents a saturated ringsystem having three to twelve carbon atoms and one to three rings.Examples of cycloalkyl groups include cyclopropyl, cyclopentyl,bicyclo(3.1.1)heptyl, adamantyl, and the like. The cycloalkyl groups ofthis invention can be optionally substituted with one, two, three, four,or five substituents independently selected from the group consisting ofalkoxy, alkoxycarbonyl, alkyl, aminoalkyl, arylalkoxy, aryloxy,arylsulfanyl, halo, haloalkoxy, haloalkyl, and hydroxy, wherein the arylpart of the arylalkoxy, the aryloxy, and the arylsulfanyl can be furtheroptionally substituted with one, two, or three substituentsindependently selected from the group consisting of alkoxy, alkyl, halo,haloalkoxy, haloalkyl, and hydroxy.

The term “cycloalkylalkoxy,” as used herein, represents a cycloalkylgroup attached to the parent molecular moiety through an alkoxy group.

The term “(cycloalkyl)alkyl,” as used herein, represents a cycloalkylgroup attached to the parent molecular moiety through an alkyl group.

The term “cycloalkylcarbonyl,” as used herein, represents a cycloalkylgroup attached to the parent molecular moiety through a carbonyl group.

The term “cycloalkyloxy,” as used herein, represents a cycloalkyl groupattached to the parent molecular moiety through an oxygen atom.

The term “formyl,” as used herein, represents —CHO.

The term “formylalkyl,” as used herein, represents a formyl groupattached to the parent molecular moiety through an alkyl group.

The term “halo,” as used herein, represents F, Cl, Br, or I.

The term “haloalkanoyl,” as used herein, represents a haloalkyl groupattached to the parent molecular moiety through a carbonyl group.

The term “haloalkoxy,” as used herein, represents a haloalkyl groupattached to the parent molecular moiety through an oxygen atom.

The term “haloalkyl,” as used herein, represents an alkyl groupsubstituted by one, two, three, or four halogen atoms.

The term “heteroalkenylene,” as used herein, represents a divalent groupof three to eight atoms derived from a straight or branched chaincontaining at least one carbon-carbon double bond that contains one ortwo heteroatoms independently selected from the group consisting ofnitrogen, oxygen, and sulfur, wherein the remaining atoms are carbon.The heteroalkenylene groups of the present invention can be attached tothe parent molecular moiety through the carbon atoms or the heteroatomsin the chain.

The term “heteroalkylene,” as used herein, represents a divalent groupof two to eight atoms derived from a saturated straight or branchedchain containing one or two heteroatoms independently selected from thegroup consisting of nitrogen, oxygen, and sulfur, wherein the remainingatoms are carbon. The heteroalkylene groups of the present invention canbe attached to the parent molecular moiety through the carbon atoms orthe heteroatoms in the chain.

The term “heterocycle,” as used herein, represents a monocyclic,bicyclic, or tricyclic ring system wherein one or more rings is a four-,five-, six-, or seven-membered ring containing one, two, or threeheteroatoms independently selected from the group consisting ofnitrogen, oxygen, and sulfur. Monocyclic ring systems are exemplified byany 3- or 4-membered ring containing a heteroatom independently selectedfrom the group consisting of oxygen, nitrogen and sulfur; or a 5-, 6- or7-membered ring containing one, two or three heteroatoms wherein theheteroatoms are independently selected from the group consisting ofnitrogen, oxygen and sulfur. The 3- and 4-membered rings have no doublebonds, the 5-membered ring has from 0-2 double bonds and the 6- and7-membered rings have from 0-3 double bonds. Representative examples ofmonocyclic ring systems include, but are not limited to, azetidine,azepine, aziridine, diazepine, 1,3-dioxolane, dioxane, dithiane, furan,imidazole, imidazoline, imidazolidine, isothiazole, isothiazoline,isothiazolidine, isoxazole, isoxazoline, isoxazolidine, morpholine,oxadiazole, oxadiazoline, oxadiazolidine, oxazole, oxazoline,oxazolidine, piperazine, piperidine, pyran, pyrazine, pyrazole,pyrazoline, pyrazolidine, pyridine, pyrimidine, pyridazine, pyrrole,pyrroline, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, tetrazine,tetrazole, thiadiazole, thiadiazoline, thiadiazolidine, thiazole,thiazoline, thiazolidine, thiophene, thiomorpholine, thiomorpholinesulfone, thiopyran, triazine, triazole, trithiane, and the like.Bicyclic ring systems are exemplified by any of the above monocyclicring systems fused to an aryl group as defined herein, a cycloalkylgroup as defined herein, a cycloalkenyl group, as defined herein, oranother monocyclic heterocycle ring system. Representative examples ofbicyclic ring system include but are not limited to, benzimidazole,benzothiazole, benzothiophene, benzoxazole, benzofuran, benzopyran,benzothiopyran, benzodioxine, 1,3-benzodioxole, cinnoline, indazole,indole, indoline, indolizine, naphthyridine, isobenzofuran,isobenzothiophene, isoindole, isoindoline, isoquinoline, phthalazine,pyranopyridine, quinoline, quinolizine, quinoxaline, quinazoline,tetrahydroisoquinoline, tetrahydroquinoline, thiopyranopyridine, and thelike. Tricyclic rings systems are exemplified by any of the abovebicyclic ring systems fused to an aryl group as defined herein, acycloalkyl group as defined herein, a cycloalkenyl group as definedherein, or another monocyclic heterocycle ring system. Representativeexamples of tricyclic ring systems include, but are not limited to,acridine, carbazole, carboline, dibenzofuran, dibenzothiophene,naphthofuran, naphthothiophene, oxanthrene, phenazine, phenoxathiin,phenoxazine, phenothiazine, thianthrene, thioxanthene, xanthene, and thelike. Heterocycle groups can be attached to the parent molecular moietythrough a carbon atom or a nitrogen atom in the group.

The heterocycle groups of the present invention can be optionallysubstituted with one, two, three, four, or five substituentsindependently selected from the group consisting of alkanoyl,alkanoylalkyl, alkenyl, alkoxy, alkoxyalkoxycarbonyl, alkoxyalkyl,alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylsulfanylalkyl, alkynyl,amino, aminoalkanoyl, aminoalkyl, aminocarbonyl, aminocarbonylalkyl,aminosulfonyl, aryl, arylalkoxyalkanoyl, arylalkoxycarbonyl, arylalkyl,arylalkylsulfonyl, arylcarbonyl, aryloxy, arylsulfanyl,arylsulfanylalkyl, arylsulfonyl, carbonyloxy, carboxy, cyano,cyanoalkyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkylcarbonyl, formyl,formylalkyl, halo, haloalkoxy, haloalkyl, heterocycle,(heterocycle)alkyl, (heterocycle)alkylidene, heterocyclecarbonyl,heterocyclecarbonylalkyl, hydroxy, hydroxyalkyl, nitro, oxo, spirocycle,spiroheterocycle, and —C(NH)NH₂; wherein the aryl; the aryl part of thearylalkylsulfonyl, the arylcarbonyl, the aryloxy, thearylalkoxyalkanoyl, the arylalkoxycarbonyl, the arylalkyl, thearylsulfanyl, the arylsulfanylalkyl, and the arylsulfonyl; theheterocycle; and the heterocycle part of the (heterocycle)alkyl, the(heterocycle)alkylidene, the heterocyclecarbonyl, and theheterocyclecarbonylalkyl can be further optionally substituted with one,two, three, four, or five substituents independently selected from thegroup consisting of alkanoyl, alkoxy, alkoxyalkoxycarbonyl,alkoxycarbonyl, alkyl, halo, haloalkoxy, haloalkyl, hydroxy,hydroxyalkyl, and nitro.

The term “(heterocycle)alkoxy,” as used herein, represents a heterocyclegroup attached to the parent molecular moiety through an alkoxy group.

The term “(heterocycle)alkyl,” as used herein, represents a heterocyclegroup attached to the parent molecular moiety through an alkyl group.

The term “(heterocycle)alkylidene,” as used herein, represents aheterocycle group attached to the parent molecular moiety through analkylidene group.

The term “heterocyclecarbonyl,” as used herein, represents a heterocyclegroup attached to the parent molecular moiety through a carbonyl group.

The term “heterocyclecarbonylalkenyl,” as used herein, represents aheterocyclecarbonyl group attached to the parent molecular moietythrough an alkenyl group.

The term “heterocyclecarbonylalkyl,” as used herein, represents aheterocyclecarbonyl group attached to the parent molecular moietythrough an alkyl group.

The term “(heterocycle)oxy,” as used herein, represents a heterocyclegroup attached to the parent molecular moiety through an oxygen atom.

The term “(heterocycle)sulfanyl,” as used herein, represents aheterocycle group attached to the parent molecular moiety through asulfur atom.

The term “(heterocycle)sulfanylalkyl,” as used herein, represents aheterocyclesulfanyl group attached to the parent molecular moietythrough an alkyl group.

The term “hydroxy,” as used herein, represents —OH.

The term “hydroxyalkyl,” as used herein, represents a hydroxy groupattached to the parent molecular moiety through an alkyl group.

The term “nitro,” as used herein, represents —NO₂.

The term “nitrogen protecting group,” as used herein, represents groupsintended to protect an amino group against undesirable reactions duringsynthetic procedures. Common N-protecting groups comprise acyl groupssuch as acetyl, benzoyl, 2-bromoacetyl, 4-bromobenzoyl,tert-butylacetyl, carboxaldehyde, 2-chloroacetyl, 4-chlorobenzoyl,a-chlorobutyryl, 4-nitrobenzoyl, o-nitrophenoxyacetyl, phthalyl,pivaloyl, propionyl, trichloroacetyl, and trifluoroacetyl; sulfonylgroups such as benzenesulfonyl, and p-toluenesulfonyl; carbamate forminggroups such as benzyloxycarbonyl, benzyloxycarbonyl (Cbz),tert-butyloxycarbonyl (Boc), p-chlorobenzyloxycarbonyl,p-methoxybenzyloxycarbonyl, and the like.

The term “oxo,” as used herein, represents (═O).

The term “spirocycle,” as used herein, represents an alkyl diradical oftwo to eight atoms, each end of which is attached to the same carbonatom of the parent molecular moiety.

The term “spiroheterocycle,” as used herein, represents a heteroalkylenediradical, each end of which is attached to the same carbon atom of theparent molecular moiety. Examples of spiroheterocycles includedioxolanyl, tetrahydrofuranyl, pyrrolidinyl, and the like.

The term “sulfinyl,” as used herein, represents —S(O)—.

The term “sulfonyl,” as used herein, represents —SO₂—.

The term “therapeutically acceptable salt,” as use herein, representsthose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like andare commensurate with a reasonable benefit/risk ratio. The salts can beprepared in situ during the final isolation and purification of thecompounds of the present invention or separately by reacting a free basegroup with a suitable organic acid. Representative acid addition saltsinclude acetate, adipate, alginate, ascorbate, aspartate,benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate,camphorsulfonate, citrate, cyclopentanepropionate, digluconate,dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate,glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide,hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate,lactate, laurate, lauryl sulfate, malate, maleate, malonate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate,oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate,phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate,tartrate, thiocyanate, toluenesulfonate, trifluoroacetate, undecanoate,valerate salts, and the like. Representative alkali or alkaline earthmetal salts include calcium, lithium, magnesium, potassium, sodium, andthe like, as well as non-toxic ammonium, quaternary ammonium, and aminecations, including, but not limited to, ammonium, dimethylamine,ethylamine, methylamine, tetraethylammonium, tetramethylammonium,triethylamine, trimethylamine, and the like.

Basic addition salts can be prepared during the final isolation andpurification of the compounds by reacting a carboxy group with asuitable base such as the hydroxide, carbonate, or bicarbonate of ametal cation or with ammonia or an organic primary, secondary, ortertiary amine. The cations of therapeutically acceptable salts includelithium, sodium, potassium, calcium, magnesium, and aluminum, as well asnontoxic quaternary amine cations such as ammonium, tetramethylammonium,tetraethylammonium, methylamine, dimethylamine, trimethylamine,triethylamine, diethylamine, ethylamine, tributylamine, pyridine,N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine,dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine,1-ephenamine, and N,N′-dibenzylethylenediamine. Other representativeorganic amines useful for the formation of base addition salts includeethylenediamine, ethanolamine, diethanolamine, piperidine, andpiperazine.

The present compounds can also exist as therapeutically acceptableprodrugs. The term “therapeutically acceptable prodrug,” refers to thoseprodrugs or zwitterions which are suitable for use in contact with thetissues of patients without undue toxicity, irritation, and allergicresponse, are commensurate with a reasonable benefit/risk ratio, and areeffective for their intended use. The term “prodrug,” refers tocompounds which are rapidly transformed in vivo to parent compounds offormula (I) for example, by hydrolysis in blood.

Asymmetric centers exist in the compounds of the present invention.These centers are designated by the symbols “R” or “S,” depending on theconfiguration of substituents around the chiral carbon atom. It shouldbe understood that the invention encompasses all stereochemical isomericforms, or mixtures thereof, which possess the bility to induceapoptosis. Individual stereoisomers of compounds can be preparedsynthetically from commercially available starting materials whichcontain chiral centers or by preparation of mixtures of enantiomericproducts followed by separation such as conversion to a mixture ofdiastereomers followed by separation or recrystallization,chromatographic techniques, or direct separation of enantiomers onchiral chromatographic columns. Starting compounds of particularstereochemistry are either commercially available or can be made andresolved by techniques known in the art.

According to methods of treatment, the compounds of the presentinvention can be useful for the prevention of metastases from the tumorsdescribed above either when used alone or in combination withradiotherapy and/or other chemotherapeutic treatments conventionallyadministered to patients for treating cancer. When using the compoundsof the present invention for chemotherapy, the specific therapeuticallyeffective dose level for any particular patient will depend upon factorssuch as the disorder being treated and the severity of the disorder; theactivity of the particular compound used; the specific compositionemployed; the age, body weight, general health, sex, and diet of thepatient; the time of administration; the route of administration; therate of excretion of the compound employed; the duration of treatment;and drugs used in combination with or coincidently with the compoundused. For example, when used in the treatment of solid tumors, compoundsof the present invention can be administered with chemotherapeuticagents such as alpha inteferon, COMP (cyclophosphamide, vincristine,methotrexate, and prednisone), etoposide, mBACOD (methortrexate,bleomycin, doxorubicin, cyclophosphamide, vincristine, anddexamethasone), PRO-MACE/MOPP (prednisone, methotrexate (w/leucovinrescue), doxorubicin, cyclophosphamide, taxol,etoposide/mechlorethamine, vincristine, prednisone, and procarbazine),vincristine, vinblastine, angioinhibins, TNP-470, pentosan polysulfate,platelet factor 4, angiostatin, LM-609, SU-101, CM-101, Techgalan,thalidomide, SP-PG, and the like. For example, a tumor may be treatedconventionally with surgery, radiation or chemotherapy and a compound ofthe present invention subsequently administered to extend the dormancyof micrometastases and to stabilize and inhibit the growth of anyresidual primary tumor.

The compounds of the present invention can be administered orally,parenterally, osmotically (nasal sprays), rectally, vaginally, ortopically in unit dosage formulations containing carriers, adjuvants,diluents, vehicles, or combinations thereof. The term “parenteral”includes infusion as well as subcutaneous, intravenous, intramuscular,and intrasternal injection.

Parenterally administered aqueous or oleaginous suspensions of thecompounds of the present invention can be formulated with dispersing,wetting, or suspending agents. The injectable preparation can also be aninjectable solution or suspension in a diluent or solvent. Among theacceptable diluents or solvents employed are water, saline, Ringer'ssolution, buffers, dilute acids or bases, dilute amino acid solutions,monoglycerides, diglycerides, fatty acids such as oleic acid, and fixedoils such as monoglycerides or diglycerides.

The chemotherapeutic effect of parenterally administered compounds canbe prolonged by slowing their absorption. One way to slow the absorptionof a particular compound is administering injectable depot formscomprising suspensions of crystalline, amorphous, or otherwisewater-insoluble forms of the compound. The rate of absorption of thecompound is dependent on its rate of dissolution which is, in turn,dependent on its physical state. Another way to slow absorption of aparticular compound is administering injectable depot forms comprisingthe compound as an oleaginous solution or suspension. Yet another way toslow absorption of a particular compound is administering injectabledepot forms comprising microcapsule matrices of the compound trappedwithin liposomes, microemulsions, or biodegradable polymers such aspolylactide-polyglycolide, polyorthoesters or polyanhydrides. Dependingon the ratio of drug to polymer and the composition of the polymer, therate of drug release can be controlled.

Transdermal patches also provide controlled delivery of the compounds.The rate of absorption can be slowed by using rate controlling membranesor by trapping the compound within a polymer matrix or gel. Conversely,absorption enhancers can be used to increase absorption.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In these solid dosage forms, the activecompound can optionally comprise diluents such as sucrose, lactose,starch, talc, silicic acid, aluminum hydroxide, calcium silicates,polyamide powder, tableting lubricants, and tableting aids such asmagnesium stearate or microcrystalline cellulose. Capsules, tablets andpills can also comprise buffering agents; and tablets and pills can beprepared with enteric coatings or other release-controlling coatings.Powders and sprays can also contain excipients such as talc, silicicacid, aluminum hydroxide, calcium silicate, polyamide powder, ormixtures thereof. Sprays can additionally contain customary propellantssuch as chlorofluorohydrocarbons or substitutes thereof

Liquid dosage forms for oral administration include emulsions,microemulsions, solutions, suspensions, syrups, and elixirs comprisinginert diluents such as water. These compositions can also compriseadjuvants such as wetting, emulsifying, suspending, sweetening,flavoring, and perfuming agents.

Topical dosage forms include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants, and transdermal patches. Thecompound is mixed under sterile conditions with a carrier and any neededpreservatives or buffers. These dosage forms can also include excipientssuch as animal and vegetable fats, oils, waxes, paraffins, starch,tragacanth, cellulose derivatives, polyethylene glycols, silicones,bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.Suppositories for rectal or vaginal administration can be prepared bymixing the compounds of the present invention with a suitablenonirritating excipient such as cocoa butter or polyethylene glycol,each of which is solid at ordinary temperature but fluid in the rectumor vagina. Ophthalmic formulations comprising eye drops, eye ointments,powders, and solutions are also contemplated as being within the scopeof the present invention.

The total daily dose of the compounds of the present inventionadministered to a host in single or divided doses can be in amounts fromabout 0.1 to about 200 mg/kg body weight or preferably from about 0.25to about 100 mg/kg body weight. Single dose compositions can containthese amounts or submultiples thereof to make up the daily dose.

Determination of Biological Activity

Assays for the inhibition of BCL-X1 were performed in 96-well microtiterplates. Compounds of the present invention were diluted in DMSO toconcentrations between 100 μM and 1 pM and introduced into each cell ofthe plate. A mixture totaling 125 μL per well of assay buffer (20 mMphosphate buffer (pH 7.4), 1 mM EDTA, 0.05% PEG-8000), 50 nM of BCL-X1protein (prepared according to the procedure described in Science 1997,275, 983-986), 5 nM fluorescein-labeled BAD peptide (purchased fromSynpep, Calif.), and the DMSO solution of the compound of the presentinvention was shaken for 2 minutes and placed in a LJL Analyst (LJL BioSystems, Calif.). A negative control (DMSO, 5 nM BAD peptide, assaybuffer) and a positive control (DMSO, 5 nM BAD peptide, 50 nM BCL-X1,assay buffer) were used to determine the range of the assay.Polarization was measured at room temperature using a continuousFluorescein lamp (excitation 485 mM, emission 530 mM). Percentage ofinhibition was determined by (1-((mP value of well-negativecontrol)/range))×100%. IC₅₀ values were calculated using MicrosoftExcel. Compounds of the present invention have IC₅₀ values between 0.011and 10 μM and are therefore useful for inhibiting BCL-X1 and treatingapoptosis-mediated diseases. Preferred compounds of the presentinvention have IC₅₀ values between 0.011 and 0.5 μM, and most preferredcompounds have IC50 values between 0.011 and 0.10 μM.

Assays for the inhibition of BCL-2 were performed in 96-well microtiterplates. Compounds of the instant invention were diluted in DMSO toconcentrations between 100 μM and 1 pM and introduced into each well ofthe plate. A mixture totaling 125 μL per well of assay buffer (20 mMphosphate buffer (pH 7.4), 1 mM EDTA, 0.05% PF-68), 30 nM of BCL-2protein (prepared according to the procedure described in PNAS 2001, 98,3012-3017), 5 nM fluorescein-labeled BAX peptide (prepared in-house),and the DMSO solution of the compound of the instant invention wasshaken for 2 minutes and placed in a LJL Analyst (LJL Bio Systems,Calif.). A negative control (DMSO, 5 nM BAX peptide, assay buffer) and apositive control (DMSO, 5 nM BAX peptide, 30 nM BCL-2, assay buffer)were used to determine the range of the assay. Polarization was measuredat room temperature using a continuous Fluorescein lamp (excitation 485mM, emission 530 mM). Percentage of inhibition was determined by (1-((mPvalue of well-negative control)/range))×100%. IC₅₀ values werecalculated using Microsoft Excel. Compounds of the present inventionhave IC₅₀ values between 0.017 and 10 μM and are therefore useful forinhibiting BCL-2 and treating apoptosis-mediated diseases. Preferredcompounds of the present invention have IC₅₀ values between 0.017 and0.5 μM, and most preferred compounds have IC50 values between 0.017 and0.20 μM.

Based upon the structural and functional similarity of the BCLantiapoptotic proteins, it is reasonable to expect that in addition toinducing apoptosis by the inhibition of BCL-X1 and BCL-2, the currentinvention may induce apoptosis through their action on otherantiapoptotic proteins in the Bcl family of proteins, such as BCL-w,BCL-b, MCL-1 and/or A1/Bfl-1.

Synthetic Methods

Abbreviations which have been used in the descriptions of the scheme andthe examples that follow are: OAc for acetate; CyMAP-1 for2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl; dba fordibenzylideneacetone; dppf for diphenylphosphinoferrocene; DMF forN,N-dimethylformamide; DME for 1,2-dimethoxyethane; THF fortetrahydrofuran; MTBE for methyl tert-butyl ether; NMP forN-methylpyrroldinone; TFP for tris-2-furylphosphine; EDCI for1-ethyl-3-(3-(dimethylamino)propyl)-carbodiimide hydrochloride; DMAP for4-dimethylaminopyridine; DCC for 1,3-dicyclohexylcarbodiimide; CDI for1,1′-carbonyldiimidazole; DMSO for dimethylsulfoxide; TFA fortrifluoroacetic acid; NaHMDS for sodium hexamethyldisilazide; LAH forlithium aluminum hydride; p-TsOH for p-toluenesulfonic acid; DIBAL-H fordiisobutylaluminum hydride; Fmoc for 9-fluorenylmethyl carbamate;Asp(OtBu)—OH for aspartic acid (4-tert-butyl ester); Lys(BOC)—OH forN_(ε)-tert-butyoxycarbonyl lysine; HOBT for 1-hydroxybenzotriazole; BOCfor tert-butoxycarbonyl; DEAD for diethyl azodicarboxylate; TBAF fortetrabutylammonium fluoride; BINAP for2,2′-bis(diphenylphosphino)-1,1′-binaphthyl; Boc-Ser-OMe forN-tert-butoxycarbonyl serine methyl ester; DMA forN,N-dimethylacetamide; and HMPA for hexamethylphosphoramide.

The compounds and processes of the present invention will be betterunderstood in connection with the following synthetic schemes whichillustrate the methods by which the compounds of the invention may beprepared. The groups R¹, R², R³, and R⁴ are as defined above unlessotherwise noted below. It will be readily apparent to one of ordinaryskill in the art that the compounds defined above can be synthesized bysubstitution of the appropriate reactants and agents in the synthesesshown below. It will also be apparent that protection and deprotectionsteps, as well as the order of the steps themselves, can be carried outin varying order to successfully complete the syntheses of compounds ofthe present invention.

This invention is intended to encompass compounds of formula (I) whenprepared by synthetic processes or by metabolic processes. Preparationof the compounds of the invention by metabolic processes include thoseoccurring in the human or animal body (in vivo) or processes occurringin vitro.

As shown in Scheme 1, compounds of formula (1) (Ar is aryl orheterocycle; X is halo; R¹¹ is alkyl) can be reacted with compounds offormula (2) (R⁴ is an unsaturated group such as aryl or alkenyl; R¹² ishydrogen or alkyl) in the presence of catalytic palladium and base toprovide compounds of formula (3). Examples of palladium catalystsinclude Pd(PPh₃)₄, Pd(OAc)₂/CyMAP-1, and Pd₂(dba)₃/AsPh₃, andPd(dppf)Cl₂.CH₂Cl₂. Representative bases include Na₂CO₃, CsF, andCs₂CO₃. Examples of solvents used in these reactions include toluene,dioxane, DMF, ethanol, DME, and mixtures thereof The reactiontemperature is about 75° C. to about 120° C. and depends on the methodchosen. Reaction times are typically about 1 to about 24 hours.

Compounds of formula (3) (R¹¹ is alkyl) can be hydrolyzed in thepresence of aqueous base to form compounds of formula (3) (R¹¹ ishydrogen). Examples of bases include LiOH, NaOH, and KOH. Representativesolvents include water, THF, dioxane, and mixtures thereof. The reactiontemperature is about 25° C. to about 60° C. and depends on the methodchosen. Reaction times are typically about 1 to about 18 hours.

An alternative synthesis of compounds of formula (3) is shown in Scheme2. Compounds of formula (4) (Ar is optionally substituted aryl oroptionally substituted heterocycle; R¹¹ is hydrogen or alkyl; R¹² ishydrogen or alkyl) can be reacted with compounds of formula (5) (R⁴ ispreviously defined; X is halo or triflate) using the conditionsdescribed in Scheme 1 to provide compounds of formula (3).

As shown in Scheme 3, compounds of formula (6) (X is F or Cl) can beconverted to compounds of formula (7) by treatment with ammoniumhydroxide. Examples of solvents used in this reaction include diethylether, THF, and MTBE. The reaction temperature is about −5° C. to about25° C. and reaction times are typically about 15 minutes to about 1hour. In a preferred embodiment, compounds of formula (6) in diethylether at 0° C. are treated with concentrated ammonium hydroxide andstirred for 30 minutes to provide compounds of formula (7).

The method chosen for the conversion of compounds of formula (7) tocompounds of formula (8) is dependent on R². Compounds of formula (8)wherein R² is —NR⁵R⁶ can be formed by treating compounds of formula (7)with the appropriately substituted amine. Examples of solvents used inthis reactions include DMF, dioxane, and NMP. Reaction temperatures areabout 35° C. to about 130° C. and reaction times are typically about 8to about 24 hours. Compounds of formula (8) wherein R² is alkoxy,alkylsulfanyl, aryloxy, arylsulfanyl, cycloalkylalkoxy, cycloalkyloxy,(heterocycle)oxy, or perfluoroalkoxy can be formed by treating compoundsof formula (7) with the appropriately substituted alcohol in thepresence of base. Representative bases include NaH/15-crown-5, and NaH,KH/18-crown-6. Examples of solvents used in this reaction include DMF,THF, NMP, and dioxane. The reaction temperature is about 20° C. to about120° C. and the reaction times are typically about 30 minutes to about24 hours.

As shown in Scheme 4, compounds of formula (8) can be reacted with1,3-dibromo-5,5-dimethylhydantoin (9) in the presence of trifluoraceticacid to provide compounds of formula (10). Examples of solvents used inthis reaction include dichloromethane, 1,2-dichloroethane, andchloroform. The reaction temperature is about 20° C. to about 35° C.,and the reaction time is typically about 6 to about 24 hours. In apreferred embodiment, compounds of formula (8) in dichloromethane atroom temperature are treated with 1,3-dibromo-5,5-dimethylhydantoin (9)and stirred for 18 hours to provide compounds of formula (10).

Compounds of formula (10) can be converted to compounds of formula (12)by coupling with compounds of formula (11) (M is SnBu₃ or B(OR¹³)₂) inthe presence of a palladium catalyst. Representative palladium catalystsinclude Pd(PPh₃)₄, Pd(dppf)Cl₂.CH₂Cl₂, and Pd₂(dba)₃/TFP. Examples ofsolvents include acetonitrile, dioxane, and DMF. The reactiontemperature is about 35° C. to about 110° C. and depends on the methodchosen. Reaction times are typically about 8 to about 48 hours.

As shown in Scheme 5, compounds of formula (3) (R¹¹ is hydrogen) can bereacted with compounds of formula (13) in the presence of an activatingagent to provide compounds of formula (14). Representative activatingagents include EDCI/DMAP, DCC/DMAP, and CDI/DMAP. Examples of solventsused in these reactions include dichloromethane, chloroform, and DMF.The reaction temperature is about 20° C. to about 40° C. and depends onthe method chosen. Reaction times are typically about 8 to about 24hours.

Scheme 6 shows the synthesis of compounds of formula (18) (a is 0-5 andeach R¹⁶ is a heterocycle substituent). Compounds of formula (14) (R¹¹is alkyl) can be reacted with compounds of formula (15) in the presenceof acetyl chloride to provide compounds of formula (16). Examples ofsolvents used in these reactions include 1,2-dichloroethane, chloroform,and carbon tetrachloride. The reaction is conducted at about 80 to about90° C. for about 1 to about 6 hours.

Conversion of compounds of formula (16) to compounds of formula (17) canbe accomplished by treatment with a reducing agent. Representativereducing agents include BF₃—Et₂O/NaBH₄ and B₂H₆. Examples of solventsused in these reactions include diethyl ether, THF, toluene, anddichloromethane. The reaction is conducted at about 0° C. to about 100°C. and reaction times are typically about 1 to about 12 hours.

Compounds of formula (17) can be converted to compounds of formula (18)following the methods described in Scheme 5.

The present invention will now be described in connection with certainpreferred embodiments which are not intended to limit its scope. On thecontrary, the present invention covers all alternatives, modifications,and equivalents as can be included within the scope of the claims. Thus,the following examples, which include preferred embodiments, willillustrate the preferred practice of the present invention, it beingunderstood that the examples are for the purposes of illustration ofcertain preferred embodiments and are presented to provide what isbelieved to be the most useful and readily understood description of itsprocedures and conceptual aspects.

Compounds of the invention were named by ACD/ChemSketch version 4.5(developed by Advanced Chemistry Development, Inc., Toronto, ON, Canada)or were given names which appeared to be consistent with ACDnomenclature.

EXAMPLE 14-((2,2-dimethylcyclopentyl)amino)-N-((4′-fluoro(1,1′-biphenyl)-4-yl)carbonyl)-3-nitrobenzenesulfonamideEXAMPLE 1A methyl 4′-fluoro(1,1′-biphenyl)-4-carboxylate

A mixture of methyl 4-bromobenzoate (21.5 g, 100 mmol),4-fluorophenylboronic acid (14.7 g, 105 mmol), Pd(dppf)Cl₂.CH₂Cl₂(1.48g, 2.0 mmol), and 2M Na₂CO₃ (100 mL) in toluene (200 mL) and was heatedto reflux, stirred for 10 hours, diluted with ethyl acetate (200 mL),washed with water (100 mL) and brine (50 mL), dried (MgSO₄), filtered,and concentrated. The concentrate was recrystallized from ethylacetate/hexanes to provide the desired product. The mother liquor wasconcentrated and purified by flash column chromatography on silica gelwith 10% ethyl acetate/hexanes to provide additional product. MS (DCI)m/e 231 (M+H)⁺.

EXAMPLE 1B 4′-fluoro(1,1′-biphenyl)-4-carboxylic acid

A room temperature solution of Example 1A (10.0 g, 43.4 mmol) andsaturated LiOH (50 mL) in THF (100 mL) was stirred for 16 hours, slowlyadjusted to pH 2-4 with 6M HCl, diluted with ethyl acetate (200 mL),washed with water (100 mL) and brine (50 mL), dried (MgSO₄), filtered,and concentrated to provide the desired product of sufficient purity forsubsequent use. MS (ESI(−)) m/e 215 (M−H)⁻.

EXAMPLE 1C 4-chloro-3-nitrobenzenesulfonamide

A 0° C. solution of 4-chloro-3-nitrobenzenesulfonyl chloride (12.8 g,50.0 mmol) in diethyl ether (1 L) was slowly treated with 0° C.concentrated NH₄OH (50 mL) and stirred for 30 minutes. The organic layerwas dried (MgSO₄), filtered, and concentrated to provide the desiredproduct of sufficient purity for subsequent use.

EXAMPLE 1D4-chloro-N-((4′-fluoro(1,1′-biphenyl)-4-yl)carbonyl)-3-nitrobenzenesulfonamide

A room temperature solution of Example 1B (4.54 g, 21.0 mmol), Example1C (4.74 g, 20.0 mmol), EDCI (4.80 g, 25.0 mmol), and DMAP (1.23 mg,10.0 mmol) in dichloromethane (60 mL) was stirred for 16 hours, dilutedwith ethyl acetate (200 mL), washed sequentially with 1M HCl (50 mL),water (50 mL) and brine (20 mL), dried (MgSO₄), filtered, andconcentrated. The concentrate was purified by flash columnchromatography on silica gel with 50% ethyl acetate/hexanes to providethe desired product. MS (ESI(−)) m/e 433 (M−H)⁻.

EXAMPLE 1E4-((2,2-dimethyleyclopentyl)amino)-N-((4′-fluoro(1,1′-biphenyl)-4-yl)carbonyl)-3-nitrobenzenesulfonamide

A solution of Example 1D (50 mg, 0.12 mmol) and2,2-dimethylcyclopentylamine (65 mg, 0.58 mmol) in DMF (2.0 mL) washeated to 120° C. in a sealed vial with shaking for 16 hours. Themixture was concentrated, dissolved in 1:1/DMSO:methanol (1.0 mL) andpurified by reverse phase preparative HPLC using 0.1% TFA in H₂O/CH₃CNto provide the desired product. MS (APCI(+)) m/e 529 (M+NH₄)⁺; ¹H NMR(500 MHz, DMSO-d₆) δ12.45 (br s, 1H), 8.69 (d, 1H), 8.49 (d, 1H), 7.99(dd, 1H), 7.97 (d, 2H), 7.80 (2d, 4H), 7.39 (d, 1H), 7.33 (t, 2H), 3.88(ddd, 1H), 2.28-2.25 (m, 1H), 1.75-1.55 (m, 5H), 1.07 (s, 3H), 1.02 (s,3H).

EXAMPLE 24-(cyclohexylamino)-N-((4′-fluoro(1,1′-biphenyl)-4yl)-carbonyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting cyclohexylamine for2,2-dimethylcyclopentylamine in Example 1E. MS (ESI(−)) m/e 496 (M−H)⁻;¹H NMR (300 MHz, CDCl₃) δ8.94 (d, 1H), 8.55 (m, 2H), 8.16 (dd, 1H), 7.83(d, 2H), 7.62 (d, 2H), 7.55 (m, 5H), 7.16 (m, 2H), 6.98 (d, 1H), 3.60(br s, 1H), 2.05 (m, 2H), 1.90-1.25 (m, 8H).

EXAMPLE 3N-((4′-bromo(1,1′-biphenyl)-4-yl)carbonyl)-4-(cyclohexylamino)-3-nitrobenzenesulfonamideEXAMPLE 3A 4-(cyclohexylamino)-3-nitrobenzenesulfonamide

A room temperature solution of Example 1C (2.36 g, 10.0 mmol) andcyclohexylamine (2.0 mL) in dioxane (5 mL) was stirred for 16 hours,diluted with ethyl acetate (100 mL), washed sequentially with 3M HCl (20mL), water (20 mL) and brine (10 mL), dried (MgSO₄), filtered, andconcentrated to provide the desired product of sufficient purity forsubsequent use.

EXAMPLE 3B 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid

A solution of 4-(dihydroxyboryl)benzoic acid (1.66 g, 10 mmol) andpinacol (12 mmol) in toluene (70 mL) was refluxed in a Dean-Starkapparatus for 16 hours and concentrated. The concentrate was trituratedwith diethyl ether and filtered to provide the desired product ofsufficient purity for subsequent use.

EXAMPLE 3C4-(cyclohexylamino)-3-nitro-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl)benzenesulfonamide

A room temperature solution of Example 3A (1.24 g, 5.0 mmol), Example 3B(1.50 g, 5.0 mmol), EDCI (1.15 g, 6.0 mmol) and DMAP (124 mg) indichloromethane (10 mL) was stirred for 16 hours, diluted with ethylacetate (100 mL), washed sequentially with 1M HCl (20 mL), water (20mL), and brine (10 mL), dried (MgSO₄), filtered, and concentrated. Theconcentrate was purified by flash column chromatography on silica gelwith 50% ethyl acetate/hexanes to provide the desired product. MS(ESI(−)) m/e 528 (M−H)⁻.

EXAMPLE 3DN-((4′-bromo(1,1′-biphenyl)-4-yl)carbonyl)-4-(cyclohexylamino)-3-nitrobenzenesulfonamide

A mixture of Example 3C (105 mg, 0.2 mmol), 4-bromo-1-iodobenzene (140mg, 0.5 mmol), Pd₂(dba)₃ (18 mg, 0.04 mmol), triphenylarsine (36 mg,0.12 mmol) and 1M Na₂CO₃ (0.5 mL) in dioxane (4 mL) was heated to 95° C.and stirred for 5 hours. The mixture was diluted with ethyl acetate (50mL), washed sequentially with 1M HCl (5 mL), water (5 mL), and brine (5mL), dried (MgSO₄), filtered, and concentrated. The concentrate waspurified by flash column chromatography on silica gel with 50% ethylacetate/hexanes to provide the desired product. MS (ESI(−)) m/e 556(M−H)⁻; ¹H NMR (400 MHz, DMSO-d₆) δ8.53 (d, 1H), 8.16 (d, 1H), 7.95 (d,2H), 7.91 (dd, 1H), 7.68-7.60 (m, 5H), 4.12 (d, 1H), 3.67 (m, 1H),2.00-1.31 (m, 10H).

EXAMPLE 44-(cyclohexylamino)-N-(4-(1H-indol-6-yl)benzoyl)-3-nitrobenzenesulfonamideEXAMPLE 4A 4-(1H-indol-6-yl)benzoic acid

A mixture of 6-bromoindole (480 mg, 2.45 mmol),4-(dihydroxyboryl)benzoic acid (406 mg, 2.45 mmol), Pd(dppf)Cl₂.CH₂Cl₂(10 mg, 0.01 mmol), and 2M Na₂CO₃ (5.6 mL, 11.2 mmol) in a mixture ofethanol (4 mL) and DMF (7 mL) was heated to 100° C., stirred for 16hours, filtered, and concentrated. The concentrate was dissolved inethyl acetate, washed sequentially with 1M H₃PO₄, water, and brine,dried (MgSO₄), filtered, and concentrated. The concentrate was purifiedby flash column chromatography on silica gel with 5%methanol/dichloromethane to provide the desired product. MS (ESI(−)) m/e236 (M−H)⁻.

EXAMPLE 4B4-(cyclohexylamino)-N-(4-(1H-indol-6-yl)benzoyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 4A and Example3A for Example 1B and Example 1C, respectively, in Example 1D. MS(ESI(+)) m/e 519 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ8.67 (m, 1H), 7.96(m, 3H), 7.82 (m, 2H), 7.68 (m, 2H), 7.48 (m, 3H), 6.47 (m, 1H), 1.96(m, 2H), 1.71 (m, 2H), 1.43 (m, 7H).

EXAMPLE 5N-(4-(4-tert-butylcyclohexyl)benzoyl)-4-(cyclohexylamino)-3-nitrobenzenesulfonamideEXAMPLE 5A 4-tert-butyl-1-cyclohexen-1-yl trifluoromethanesulfonate

A −78° C. solution of 4-tert-butylcyclohexanone (1.54 g, 10 mmol) andN-phenyl(trifluoromethanesulfonamide) (3.75 g, 10.5 mmol) in THF (20mmol) was treated with 1M NaHMDS in THF (11 mL), warmed to roomtemperature, filtered through a pad of silica gel (10 g) with diethylether (5 mL), and concentrated. The concentrate was purified by flashcolumn chromatography on silica gel with 1% ethyl acetate/hexanes toprovide the desired product.

EXAMPLE 5B methyl 4-(4-tert-butyl-1-cyclohexen-1-yl)benzoate

A mixture of Example 5A (286 mg, 1.0 mmol),(4-methoxycarbonylphenyl)-boronic acid (216 mg, 1.2 mmol),Pd(dppf)Cl₂.CH₂Cl₂ (37 mg, 0.05 mmol), and cesium fluoride (454 mg, 3.0mmol) in dioxane (5 mL) was heated to 90° C., stirred for 16 hours,filtered through a pad of silica gel (10 g) with diethyl ether (5 mL)and concentrated. The concentrate was purified by flash columnchromatography on silica gel with 5% ethyl acetate/hexanes to providethe desired product.

EXAMPLE 5C methyl 4-(4-tert-butylcyclohexyl)benzoate

A room temperature mixture of Example 5B (230 mg, 0.84 mmol) and 10%Pd/C (100 mg) in ethyl acetate (5 mL) was stirred under a hydrogenatmosphere for 3 hours, filtered through a pad of silica gel (10 g) withdiethyl ether (10 mL), and concentrated to provide the desired productas a ˜2:1 mixture of diastereomers. MS (DCI) m/e 275 (M+H)⁺.

EXAMPLE 5DN-(4-(4-tert-butylcyclohexyl)benzoyl)-4-(cyclohexylamino)-3-nitrobenzenesulfonamide

A mixture of Example 5C (55 mg, 0.20 mmol) and 1M LiOH (0.3 mL) in THF(2 mL) was heated to 50° C., stirred for 3 hours, concentrated,dissolved in DMF (0.5 mL), and treated with a mixture of Example 3A (60mg, 0.20 mmol), EDCI (96 mg, 0.50 mmol), and DMAP (10 mg) in dioxane(2.0 mL). The mixture was stirred for 16 hours, diluted with ethylacetate (50 mL), washed sequentially with 1M HCl (5 mL), water (5 mL),and brine (5 mL), dried (MgSO₄), filtered, and concentrated. Theconcentrate was purified by flash column chromatography on silica gel,with 50% ethyl acetate/hexanes to provide a ˜2:1 mixture ofdiastereomers. MS (ESI(−)) m/e 540 (M−H)⁻; ¹H NMR (400 MHz, DMSO-d₆)δ8.63 (2d, 1H total), 8.33 (2d, 1H total), 7.95 (m, 1H), 7.82 and 7.78(2d, 2H total), 7.45 (m, 1H), 7.30 (m, 2H), 3.71 (m, 1H), 2.28-0.95 (m,20H), 0.86 and 0.75 (2s, 9H total).

EXAMPLE 66-(cyclohexylamino)-N-((4′-fluoro(1,1′-biphenyl)-4-yl)carbonyl)-5-nitro(1,1′-biphenyl)-3-sulfonamideEXAMPLE 6A 3-bromo-4-(cyclohexylamino)-5-nitrobenzenesulfonamide

A room temperature solution of Example 3A (1.81 g, 6.0 mmol) and1,3-dibromo-5,5-dimethylhydantoin (950 mg, 3.3 mmol) in dichloromethanewas treated with trifluoracetic acid (796 uL, 9.0 mmol), stirred indarkness for 18 hours, treated with saturated NaHCO₃, and extracted withdiethyl ether. The combined extracts were washed with brine, dried(Na₂SO₄), and concentrated. The concentrate was purified by flash columnchromatography on silica gel with 15% ethyl acetate/hexanes to providethe desired product. MS (ESI(−)) m/e 376 (M−H)⁻.

EXAMPLE 6B 6-(cyclohexylamino)-5-nitro(1,1′-biphenyl)-3-sulfonamide

The desired product was prepared by substituting Example 6A andphenylboronic acid for Example 5A and 4-(methoxycarbonylphenyl)boronicacid, respectively, in Example 5B. MS (ESI(−)) m/e 374 (M−H)⁻.

EXAMPLE 6C6-(cyclohexylamino)-N-((4′-fluoro(1,1′-biphenyl)-4-yl)carbonyl)-5-nitro(1,1′-biphenyl)-3-sulfonamide

The desired product was prepared by substituting Example 6B for Example1C in Example 1D. MS (ESI(−)) m/e 572 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆)δ8.66 (d, 1H), 7.95 (m, 3H), 7.78 (m, 4H), 7.75 (d, 1H), 7.50 (m, 5H),7.31 (m, 2H), 1.60-1.41 (m, 4H), 1.32 (m, 2H), 1.12-0.96 (m, 2H),0.75-0.60 (m, 2H).

EXAMPLE 7N-((4′-fluoro(1,1′-biphenyl)-4-yl)carbonyl)-3-nitro-4-((trans-2-(phenylsulfanyl)cyclohexyl)amino)benzenesulfonamideEXAMPLE 7A trans-2-(phenylsulfanyl)cyclohexanol

A room temperature solution of cyclohexene oxide (9.81 g, 100 mmol) andN,N-diisopropylethylamine (2.60 g, 20.0 mmol) in 1,2-dichloroethane (200mL) was treated with thiophenol (11 g, 100 mmol), stirred for 16 hours,and concentrated. The concentrate was purified by flash columnchromatography on silica gel with 20% ethyl acetate/hexanes to providethe desired product.

EXAMPLE 7B ((trans-2-azidocyclohexyl)sulfanyl)benzene

A 0° C. solution of Example 7A (1.04 g, 5.0 mmol), andN,N-diisopropylethylamine (1.1 mL, 6.5 mmol) in dichloromethane (20 mL)was treated with methanesulfonyl chloride (0.46 mL, 6.0 mmol), warmed toroom temperature, stirred for 16 hours, diluted with hexanes (20 mL),filtered through a pad of silica gel (15 g) with 10% diethyl ether inhexanes, and concentrated. The concentrate was dissolved in DMF (10 mL),treated with tetrabutylammonium iodide (400 mg, 1.1 mmol), 15-crown-5(100 mg, 0.40 mmol), and sodium azide (1.0 g, 15.4 mmol), heated to 100°C., and stirred for 16 hours. The mixture was diluted with ethyl acetate(100 mL), washed with water (15 mL) and brine (15 mL), dried (MgSO₄),filtered, and concentrated. The concentrate was purified by flash columnchromatography on silica gel with 5% ethyl acetate/hexanes to providethe desired product. MS (DCI) m/e 234 (M+H)⁺.

EXAMPLE 7C trans-2-(phenylsulfanyl)cyclohexanamine

A room temperature solution of Example 7B (777 mg, 3.3 mmol),triphenylphosphine (2.62 g, 10.0 mmol), and water (180 mg, 10 mmol) inTHF (5 mL) was stirred for 16 hours and concentrated. The concentratewas purified by flash column chromatography on silica gel with 50% ethylacetate/hexanes followed by 10% methanol/dichloromethane to provide thedesired product. MS (DCI) m/e 208 (M+H)⁺.

EXAMPLE 7DN-((4′-fluoro(1,1′-biphenyl)-4-yl)carbonyl)-3-nitro-4-((trans-2-(phenylsulfanyl)cyclohexyl)amino)benzenesulfonamide

A solution of Example 7C (50 mg, 0.24 mmol), Example 1D (50 mg, 0.11mmol) and 2,6-lutidine (50 mg, 0.47 mmol) in dioxane (5 mL) was heatedto reflux, stirred for 16 hours, cooled to room temperature, filteredthrough a pad of silica gel (5 g) with 5% methanol/ethyl acetate, andconcentrated. The concentrate was purified by flash columnchromatography on silica gel with 30-100% ethyl acetate/hexanes toprovide the desired product. MS (ESI(−)) m/e 604 (M−H)⁻; ¹H NMR (400MHz, DMSO-d₆) δ8.54 (d, 1H), 8.45 (d, 1H), 7.97 (d, 2H), 7.93 (m, 1H),7.78 (m, 3H), 7.44-7.10 (m, 9H), 3.85 (m, 1H), 3.61 (m, 1H), 2.15-1.30(m, 8H).

EXAMPLE 8N-((4′-fluoro(1,1′-biphenyl)-4-yl)carbonyl)-3-nitro-4-(((1S,2R)-2-(phenylsulfanyl)cyclohexyl)amino)benzenesulfonamideEXAMPLE 8A (2RS)-2-(phenylsulfanyl)cyclohexanone

A −40° C. solution of 2M oxalyl chloride in dichloromethane (10 mL) indichloromethane (20 mL) was slowly treated with DMSO (3.12 g, 40 mmol),stirred for 30 minutes, treated with Example 7A (1.80 g, 8.6 mmol),stirred for 1 hour, and treated with triethylamine (10.1 g, 100 mmol).The mixture was warmed to room temperature, stirred for 16 hours,diluted with diethyl ether (100 mL), washed with water (15 mL) and brine(5 mL), dried (MgSO₄), filtered, and concentrated. The concentrate waspurified by flash column chromatography on silica gel with 10-25% ethylacetate/hexanes to provide the desired product. MS (DCI/NH₃) m/e 224(M+NH₄)⁺.

EXAMPLE 8B cis-2-(phenylsulfanyl)cyclohexanamine

A room temperature solution of Example 8A (847 mg, 4.1 mmol) andhydroxylamine hydrochloride (1.0 g, 14.4 mmol) in methanol (5 mL) wasstirred for 3 hours, diluted with ethyl acetate (50 mL), washed withwater (5 mL) and brine (5 mL), dried (MgSO₄), filtered, andconcentrated. The concentrate was treated with 1M LAH in THF (5 mL, 5.0mmol), stirred for 16 hours, carefully added to ice cold saturatedNaH₂PO₄ (10 mL), and extracted with ethyl acetate. The combined extractswere washed with brine (20 mL), dried (MgSO₄), filtered, andconcentrated. The concentrate was purified by flash columnchromatography on silica gel with 2-5% methanol/dichloromethane toprovide the desired product as a 3.3:1 mixture of cis- andtrans-isomers. MS (DCI) m/e 208 (M+H)⁺.

EXAMPLE 8CN-((4′-fluoro(1,1′-biphenyl)-4-yl)carbonyl)-3-nitro-4-((cis-2-(phenylsulfanyl)cyclohexyl)amino)benzenesulfonamide

Example 8B was processed according to the procedure described in Example7D to provide a 2:1 mixture of the desired product and Example 7D. MS(ESI(−) m/e 604 (M−H)⁻; ¹H NMR (400 MHz, DMSO-d₆) δ8.67 (2d, 1H total),8.56 and 8.49 (2d, 1H total), 7.97 (dt, 1H), 7.91 (dt, 1H), 7.78 (m,3H), 7.38-7.05 (m, 9H), 4.15 (m, 1H), 3.90 (m, 1H), 2.00-1.20 (m, 8H).

EXAMPLE 9N-(4-(1-cyclohexen-1-yl)benzoyl)-3-nitro-4-(((1R,2R)-2-(phenylsulfanyl)cyclohexyl)amino)benzenesulfonamideEXAMPLE 9A methyl 4-(1-cyclohexen-1-yl)benzoate

The desired product was prepared by substituting cyclohexanone fortert-butylcyclohexanone in Examples 5A and 5B. MS (DCI) m/e 217 (M+H⁺).

EXAMPLE 9B4-chloro-N-(4-(1-cyclohexen-1-yl)benzoyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 9A and Example1C for Example 5C and Example 3A, respectively, in Example 5D. MS(ESI(−)) m/e 419 (M−H)⁻.

EXAMPLE 9CN-(4-(1-cyclohexen-1-yl)benzoyl)-3-nitro-4-(((1R,2R)-2-(phenylsulfanyl)cyclohexyl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 9B for Example1D in Example 7D. MS (ESI(−)) m/e 590 (M−H)⁻; ¹H NMR (400 MHz, DMSO-d₆)δ8.51 (d, 1H), 8.42 (d, 1H), 7.90 (dd, 1H), 7.53 (d, 2H), 7.50 (m, 2H),7.40 (m, 1H), 7.20-7.09 (m, 5H), 6.32 (m, 1H), 3.85 (m, 1H), 3.61 (m,1H), 2.40-1.20 (m, 16H).

EXAMPLE 10N-(4-(1-cyclohexen-1-yl)benzoyl)-3-nitro-4-((cis-2-(phenylsulfanyl)cyclohexyl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 9B and Example8B for Example 1D and Example 7C, respectively, in Example 7D. MS(ESI(−)) m/e 590 (M−H)⁻; ¹H NMR (400 MHz, DMSO-d₆) δ8.69 (d, 1H), 8.54(d, 1H), 7.90 (dd, 1H), 7.84 (d, 2H), 7.51 (d, 2H), 7.27 (m, 3H),7.13-7.00 (m, 3H), 6.33 (m, 1H), 4.15 (m, 1H), 3.90 (m, 1H), 2.39 (m,2H), 2.20 (m, 2H), 1.95 (m, 2H), 1.90-1.20 (m, 10H).

EXAMPLE 114-(((1S,2S)-2-(benzyloxy)cyclohexyl)amino)-N-(4-(1-cyclohexen-1-yl)benzoyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 9B and(1S,2S)-2-benzyloxycyclohexylamine for Example 1D and Example 7C,respectively, in Example 7D. MS (ESI(−)) m/e 588 (M−H)⁻; ¹H NMR (400MHz, DMSO-d₆) δ8.90 (d, 1H), 8.55 (d, 1H), 8.51 (s, 1H), 8.06 (dd, 1H),7.68 (d, 2H), 7.44 (d, 2H), 7.21 (m, 2H), 7.12 (m, 3H), 6.28 (m, 1H),4.61 (d, 1H), 4.39 (d, 1H), 3.60 (m, 1H), 3.35 (m, 1H), 2.40 (m, 2H),2.23 (m, 2H), 1.90-0.80 (m, 12H).

EXAMPLE 124-(cycloheptylamino)-N-((4′-fluoro(1,1′-biphenyl)-4-yl)carbonyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting cycloheptylamine for2,2-dimethylcyclopentylamine in Example 1E. MS (APCI(+)) m/e 512 (M+H)⁺;¹H NMR (500 MHz, DMSO-d₆) δ12.45 (br s, 1H), 8.67 (d, 1H), 8.39 (d, 1H),7.99 (dd, 1H), 7.95 (d, 2H), 7.78 (2d, 4H), 7.32 (t, 2H), 7.23 (d, 1H),3.89 (ddddd, 1H), 1.98-1.92 (m, 2H), 1.71-1.52 (m, 10H).

EXAMPLE 134-((2RS)-bicyclo(2.2.1)hept-2-ylamino)-N-((4′-fluoro(1,1′-biphenyl)-4-yl)carbonyl)-3-nitrobenzenesulfonamide

A solution of Example 1D (50 mg, 0.12 mmol), 2-aminonorbornanehydrochloride (106 mg, 0.58 mmol), and triethylamine (0.08 ml, 0.58mmol) in DMF (2 mL) were heated to 120° C. in a sealed vial with shakingfor 16 hours, then concentrated. The concentrate was dissolved in1:1/DMSO:methanol (1.0 ml) and purified by reverse phase preparativeHPLC with 0.1% TFA in H₂O/CH₃CN to provide the desired product. MS(APCI(+)) m/e 510 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ12.45 (br s, 1H),8.67 (d, 1H), 8.48 (d, 1H), 7.99 (dd, 1H), 7.95 (d, 2H), 7.78 (2d, 4H),7.32 (t, 2H), 7.24 (d, 1H), 4.04 (m, 1H), 2.58 (m, 1H), 2.27 (m, 1H),2.24-2.21 (m, 1H), 1.59-1.29 (m, 6H), 0.97 (dt, 1H).

EXAMPLE 14N-((4′-fluoro(1,1′-biphenyl)-4-yl)carbonyl)-3-nitro-4-(((1R,2R,3R,5S)-2,6,6-trimethylbicyclo(3.1.1)hept-3-yl)amino)benzenesulfonamide

The desired product was prepared by substituting(1R,2R,3R,5S)-(−)-isopinocampheylamine for 2,2-dimethylcyclpentylaminein Example 1E. MS (APCI(+)) m/e 552 (M+H)⁺; ¹ H NMR (500 MHz, DMSO-d₆)δ12.45 (br s, 1H), 8.68 (d, 1H), 8.38 (d, 1H), 7.98 (dd, 1H), 7.96 (d,2H), 7.79 (2d, 4H), 7.37 (d, 1H), 7.32 (t, 2H), 4.07-4.01 (m, 1H),2.76-2.71 (m, 1H), 2.42-2.37 (m, 1H), 2.11-2.08 (m, 1H), 1.98-1.96 (m,1H), 1.95-1.86 (m, 1H), 1.67-1.63 (m, 1H), 1.24 (s, 3H), 1.13 (d, 3H),1.08 (s, 3H), 1.07 (s, 1H).

EXAMPLE 15N-((4′-fluoro(1,1′-biphenyl)-4-yl)carbonyl)-3-nitro-4-(((1R,2R,4R)-1,7,7-trimethylbicyclo(2.2.1)hept-2-yl)amino)benzenesulfonamide

The desired product was prepared by substituting (R)-(+)-bornylamine for2,2-dimethylcyclopentylamine in Example 1E. MS (APCI(+)) m/e 569(M+NH₄)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ12.55 (br s, 1H), 8.73 (d, 1H),8.70 (d, 1H), 7.98 (dd, 1H), 7.97 (d, 2H), 7.80 (2d, 4H), 7.34 (t, 2H),7.31 (d, 1H), 3.98-3.95 (m, 1H), 2.58-2.54 (m, 1H), 1.82-1.68 (m, 3H),1.58-1.51 (m, 1H), 1.29-1.25 (m, 1H), 1.02 (s, 3H), 0.98 (dd, 1H), 0.94(s, 3H), 0.90 (s, 3H).

EXAMPLE 16N-((4′-fluoro(1,1′-biphenyl)-4-yl)carbonyl)-3-nitro-4-(((1S,2S,4S)-1,7,7-trimethylbicyclo(2.2.1)hept-2-yl)amino)benzenesulfonamide

(S)-(−)-Bornylamine was processed according to the procedure describedin Example 1E to provide the desired product. MS (DCI/NH₃) m/e 569(M+NH₄)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ12.45 (br s, 1H), 8.71 (d, 1H),8.67 (t, 1H), 7.98 (dd, 1H), 7.95 (d, 2H), 7.78 (2d, 4H total), 7.32 (t,2H), 7.28 (2d, 1H total), 3.97-3.91 and 3.70-3.66 (2m, 1H total),2.56-2.50 (m, 1H), 2.06-0.95 (m, 6H), 1.01 and 1.00 (2s, 3H total), 0.95and 0.91 (2s, 3H total), 0.88 and 0.87 (2s, 3H total).

EXAMPLE 17N-(4-(2-methyl-1,3-benzothiazol-5-yl)benzoyl)-3-nitro-4-(((1S,2S,4S)-1,7,7-trimethylbicyclo(2.2.1)hept-2-yl)amino)benzenesulfonamideEXAMPLE 17A 4-(2-methyl-1,3-benzothiazol-5-yl)benzoic acid

The desired product was prepared by substituting5-bromo-2-methyl-1,3-benzothiazole for 6-bromoindole in Example 4A. MS(DCI) m/e 270 (M+H)⁺.

EXAMPLE 17B3-nitro-4-(((1S,2S,4S)-1,7,7-trimethylbicyclo(2.2.1)hept-2-yl)amino)benzenesulfonamide

The desired product was prepared by substituting (S)-(−)-bornylamine forcyclohexylamine in Example 3A. MS (ESI(−)) m/e 352 (M−H)⁻;

EXAMPLE 17CN-(4-(2-methyl-1,3-benzothiazol-5-yl)benzoyl)-3-nitro-4-(((1S,2S,4S)-1,7,7-trimethylbicyclo(2.2.1)hept-2-yl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 17A and Example17B for Example 1B and Example 1C, respectively, in Example 1D. MS(ESI(−)) m/e 603 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ8.72 (d, 1H), 8.68(d, 1H), 8.26 (d, 1H), 8.14 (d, 1H), 7.98 (m, 3H), 7.89 (d, 2H), 7.77(dd, 1H), 7.30 (d, 1H), 3.94 (m, 1H), 2.82 (s, 3H), 1.82-1.64 (m, 3H),1.54 (m, 1H), 1.25 (m, 2H), 1.00 (s, 3H), 0.92 (m, 1H), 0.91 (s, 3H),0.89 (s, 3H).

EXAMPLE 184-(1-adamantylamino)-N-((4′-fluoro(1,1′-biphenyl)-4-yl)carbonyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting 1-adamantanamine for2,2-dimethylcyclopentylamine in Example 1E. MS (APCI(+)) m/e 550 (M+H)⁺;¹H NMR (500 MHz, DMSO-d₆) δ12.45 (br s, 1H), 8.68 (d, 1H), 8.48 (s, 1H),7.96 (d, 2H), 7.95 (dd, 1H), 7.78 (2d, 4H), 7.58 (d, 1H), 7.32 (t, 2H),2.13-2.08 (m, 9H), 1.76-1.60 (m, 6H).

EXAMPLE 19N-((4′-fluoro(1,1′-biphenyl)-4-yl)carbonyl)-3-nitro-4-(2-phenoxyanilino)benzenesulfonamideEXAMPLE 19A 3-nitro-4-(2-phenoxyanilino)benzenesulfonamide

A −78° C. solution of Example 1C (236 mg, 1.0 mmol) and 2-phenoxyaniline(370 mg, 2.0 mmol) in THF (10 mL) was treated with 1M lithiumhexamethyldisilazide in THF (4 mL, 4.0 mmol), warmed to room temperatureover 4 hour, diluted with ethyl acetate (50 mL), washed sequentiallywith 1M HCl (5 mL), water (5 mL), and brine (5 mL), dried (MgSO₄),filtered, and concentrated. The concentrate was purified by flash columnchromatography on silica gel with 10-30% ethyl acetate/hexanes toprovide the desired product. MS (ESI(−)) m/e 384 (M−H)⁻.

EXAMPLE 19BN-((4′-fluoro(1,1′-biphenyl)-4-yl)carbonyl)-3-nitro-4-(2-phenoxyanilino)benzenesulfonamide

The desired product was prepared by substituting Example 19A for Example1C in Example 1D. MS (ESI(−)) m/e 582 (M−H)⁻; ¹H NMR (400 MHz, DMSO-d₆)δ9.74 (s, 1H), 8.63 (d, 1H), 7.97 (m, 3H), 7.79 (m, 4H), 7.52 (dd 1H),7.40-7.20 (m, 6H), 7.14-7.00 (m, 3H), 6.83 (m, 2H).

EXAMPLE 20N-((4′-fluoro(1,1′-biphenyl)-4-yl)carbonyl)-3-nitro-4-(2-(phenylsulfanyl)anilino)benzenesulfonamideEXAMPLE 20A 2-(phenylsulfanyl)aniline

A room temperature solution of 2-fluoronitrobenzene (1.41 g, 10.0 mmol),thiophenol (1.21 g, 11.0 mmol), and triethylamine (2 mL) in THF (20 mL)was stirred for 16 hours, treated with 3M HCl (10 mL) and tin(II)chloride dihydrate (11.4 g, 50 mmol), stirred for 4 hour, and extractedwith ethyl acetate (50 mL). The combined extracts were dried (MgSO₄),filtered, and concentrated. The concentrate was purified by flash columnchromatography on silica gel with 50% hexanes/dichloromethane to providethe desired product. MS (DCI) m/e 202 (M+H)⁺.

EXAMPLE 20B 3-nitro-4-(2-(phenylsulfanyl)anilino)benzenesulfonamide

The desired product was prepared by substituting Example 20A for2-phenyoxyaniline in Example 19A. MS (ESI(−)) m/e 400 (M−H)⁻.

EXAMPLE 20CN-((4′-fluoro(1,1′-biphenyl)-4-yl)carbonyl)-3-nitro-4-(2-(phenylsulfanyl)anilino)benzenesulfonamide

The desired product was prepared by substituting Example 20B for Example1C in Example 1D. MS (ESI(−)) m/e 598 (M−H)⁻; ¹H NMR (400 MHz, DMSO-d₆)δ9.91 (s, 1H), 8.68 (d, 1H), 7.97 (d, 2H), 7.93 (dd, 1H), 7.81 (m, 4H),7.49 (m, 2H), 7.41-7.23 (m, 8H), 7.17 (m, 1H), 6.97 (d, 1H).

EXAMPLE 214-((cyclohexylmethyl)amino)-N-((2′-methoxy(1,1′-biphenyl)-4-carbonyl)-3-nitrobenzenesulfonamideEXAMPLE 21A 2′-methoxy(1,1′-biphenyl)-4-carboxylic acid

The desired product was prepared by substituting 2-methoxyphenylboronicacid for 4-methoxyphenylboronic acid in Example 31A. MS (APCI(+)) m/e246 (M+NH₄)⁺; ¹H NMR (500 MHz, DMSO-₆) δ12.89 (br s, 1H), 7.96 (d, 2H),7.60 (d, 2H), 7.39 (ddd, 1H), 7.33 (dd, 1H), 7.14 (dd, 1H), 7.05 (dt,1H), 3.78 (s, 3H).

EXAMPLE 21B 4-((cyclohexylmethyl)amino)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting cyclohexylmethylaminefor cyclohexylamine in Example 3A. MS (DCI) m/e 314 (M+H)⁺.

EXAMPLE 21C4-((cyclohexylmethyl)amino)-N-((2′-methoxy(1,1′-biphenyl)-4-yl)carbonyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 21A and Example21B for Example 1B and Example 1C, respectively, in Example 1D. MS(APCI(+)) m/e 524 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ12.45 (br s, 1H),8.66 (d, 1H), 8.63 (t, 1H), 7.96 (dd, 1H), 7.90 (d, 2H), 7.57 (d, 2H),7.38 (dt, 1H), 7.31 (dd, 1H), 7.26 (d, 1H), 7.13 (d, 1H), 7.04 (t, 1H),3.76 (s, 3H), 3.36-3.26 (m, 2H), 1.76-1.61 (m, 6H), 1.23-1.12 (m, 3H),1.04-0.96 (m, 2H).

EXAMPLE 224-((cyclohexylmethyl)amino)-N-((4′-fluoro(1,1′-biphenyl)-4-yl)carbonyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 21B for Example1C in Example 1D. MS (ESI(−)) m/e 510 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆)δ8.68 (d, 1H); 7.94 (m, 3H), 7.82-7.74 (m, 4H), 7.36-7.26 (m, 3H), 3.16(t, 1H), 1.80-1.50 (m, 6H), 1.30-0.90 (m, 6H).

EXAMPLE 23N-((4′-chloro-3′-(trifluoromethoxy)(1,1′-biphenyl)-4-yl)carbonyl)-4-((cyclohexylmethyl)amino)-3-nitrobenzenesulfonamideEXAMPLE 23A 4-bromo-1-chloro-2-(trifluoromethoxy)benzene

A mixture of tert-butyl nitrite (1.78 mL, 15.0 mmol), copper (II)chloride (1.61 g, 12.0 mmol) and 4-bromo-2-(trifluoromethoxy)aniline(2.56 g, 10.0 mmol) in acetonitrile (40 mL) was heated to 70° C.,stirred for 3 hours, cooled to room temperature, poured into 0.5M HCl,and extracted with diethyl ether. The combined extracts were washed withwater and brine, dried (MgSO₄), filtered, and concentrated to providethe desired product. MS (ESI(+)) m/e 275 (M+H)⁺.

EXAMPLE 23B 4′-chloro-3′-(trifluoromethoxy)(1,1′-biphenyl)-4-carboxylicacid

The desired product was prepared by substituting Example 23A for6-bromoindole in Example 4A. MS (ESI(−)) m/e 315 (M−H)⁻.

EXAMPLE 23CN-((4′-chloro-3′-(trifluoromethoxy)(1,1′-biphenyl)-4-yl)carbonyl)-4-((cyclohexylmethyl)amino)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 23B and Example21B for Example 1B and Example 1C, respectively, in Example 1D. MS(ESI(−)) m/e 610 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ8.66 (m, 2H), 7.92(m, 7H), 7.27 (m, 1H), 3.32 (m, 2H), 1.70 (m, 6H), 1.19 (m, 3H), 1.02(m, 2H).

EXAMPLE 244-((cyclohexylmethyl)amino)-N-(4-(1H-indol-6-yl)benzoyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 4A and Example21B for Example 1B and Example 1C in Example 1D. MS (ESI(−)) m/e 531(M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ8.64 (m, 1H), 7.95 (m, 3H), 7.78 (m,2H), 7.70 (m, 1H), 7.63 (m, 1H) 7.42 (m, 1H), 7.38 (m, 1H), 7.24 (m,1H), 6.48 (m, 1H), 3.23 (m, 2H), 1.70 (m, 8H), 1.21 (m, 1H), 1.01 (m,2H).

EXAMPLE 254-((cyclohexylmethyl)amino)-N-(4-(2-methyl-1,3-benzothiazol-5-yl)benzoyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 17A and Example21B for Example 1B and Example 1C, respectively, in Example 1D. MS(ESI(−)) m/e 563 (M−H)⁻; ¹H NMR (400 MHz, DMSO-d₆) δ8.69 (d, 1H), 8.65(t, 1H), 8.26 (s, 1H), 8.14 (d, 1H), 7.98 (m, 3H), 7.90 (d, 2H), 7.77(dd, 1H), 7.28 (d, 1H), 3.30 (t, 2H), 2.82 (s, 3H), 1.80-1.60 (m, 6H),1.40-0.95 (m, 5H).

EXAMPLE 264-((cyclohexylmethyl)amino)-N-((4′-fluoro(1,1′-biphenyl)-4-yl)carbonyl)-3-nitro-5-(2-pyrimidinyl)benzenesulfonamideEXAMPLE 26A3-bromo-4-((cyclohexylmethyl)amino)-5-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 21B for Example3A in Example 6A. MS (ESI(+)) m/e 392 (M+H)⁺.

EXAMPLE 26B4-((cyclohexylmethyl)amino)-3-nitro-5-(2-pirimidinyl)benzenesulfonamide

A solution of Example 26A (270 mg, 0.69 mmol),2-(tributylstannyl)pyrimidine (305 uL, 0.83 mmol), Pd₂(dba)₃ (32 mg,0.034 mmol), and tris-(2-furyl)phosphine (32 mg, 0.10 mmol) inacetonitrile (2 mL) was heated to reflux for 48 hours and concentrated.The concentrate was purified by flash column chromatography on silicagel with 50% ethyl acetate/hexanes to provide the desired product. MS(ESI(+)) m/e 392 (M+H)⁺.

EXAMPLE 26C4-((cyclohexylmethyl)amino)-N-((4′-fluoro(1,1′-biphenyl)-4-yl)carbonyl)-3-nitro-5-(2-pyrimidinyl)benzenesulfonamide

The desired product was prepared by substituting Example 26B for Example1C in Example 1D. MS (ESI(+)) m/e 590 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆)δ8.04-7.90 (m, 4H); 7.82-7.70 (m, 6H), 7.31 (m, 2H), 7.05 (dd, 1H), 2.73(t, 2H), 1.70-1.53 (m, 6H), 1.52 (m, 1H), 1.16-1.07 (m, 2H), 0.92-0.79(m, 2H).

EXAMPLE 27N-((4′-fluoro(1,1′-biphenyl)-4-yl)carbonyl)-3-nitro-4-(((cis-2-(phenylsulfanyl)cyclohexyl)methyl)amino)benzenesulfonamideEXAMPLE 27AN-((4′-fluoro(1,1′-biphenyl)-4-yl)carbonyl)-4-(((trans-2-hydroxycyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 1D andtrans-2-methyl-aminocyclohexanol for Example 1C and cyclohexylamine,respectively, in Example 3A. MS (ESI(+)) m/e 528 (M+H)⁺.

EXAMPLE 27BN-((4′-fluoro(1,1′-biphenyl)-4-yl)carbonyl)-3-nitro-4-(((cis-2-(phenylsulfanyl)cyclohexyl)methyl)amino)benzenesulfonamide

A room temperature solution of tri-n-butylphosphine (90 μL, 0.36 mmol)and 1,1′-(azodicarbonyl)dipiperidine (91 mg, 0.36 mmol) in THF (4 mL)was treated with Example 27A (90 mg, 0.17 mmol) and thiophenol (21 mg,0.19 mmol), stirred for 18 hours, and concentrated. The concentrate waspurified by flash column chromatography on silica gel with 50% ethylacetate/hexanes to provide the desired product. MS (ESI(−)) m/e 618(M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ8.61 (d, 1H), 7.94 (m, 2H), 7.90 (d,1H), 7.73 (m, 2H), 7.68-7.55 (m, 7H), 7.29 (d, 2H), 6.87 (d, 1H), 3.44(m, 2H), 1.59 (m, 4H), 1.37 (m, 4H), 0.89 (m, 2H).

EXAMPLE 284-((1-adamantylmethyl)amino)-N-(4-iodobenzoyl)-3-nitrobenzenesulfonamideEXAMPLE 28A4-((1-adamantylmethyl)amino)-N-(4-iodobenzoyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting 1-adamantylmethylaminefor cyclohexylamine in Example 3A. MS (DCI) m/e 366 (M+H)⁺.

EXAMPLE 28B4-((1-adamantylmethyl)amino)-N-(4-iodobenzoyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting 4-iodobenzoic acid andExample 28A for Example 1B and Example 1C, respectively, in Example 1D.MS (ESI(−)) m/e 594 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ8.51 (d, 1H),8.40 (t, 1H), 7.87 (dd, 1H), 7.72-7.62 (q, 4H), 7.16 (d, 1H), 3.12 (d,2H), 1.97 (m, 2H), 1.72-1.54 (m, 13H).

EXAMPLE 294-((1-adamantylmethyl)amino)-N-(4-(2-chloro-3-thienyl)benzoyl)-3-nitrobenzenesulfonamideEXAMPLE 29A 4-(2-chloro-3-thienyl)-benzoic acid

Solid Pd(PPh₃)₄ (11.0 mg, 0.01 mmol) was treated with a room temperaturesolution of 2-bromo-5-chlorothiophene (143 mg, 0.72 mmol) in DME (4 mL),stirred for 5 minutes, treated with a solution of4-(dihydroxyboryl)benzoic acid (100 mg, 0.60 mmol) in DME (2 mL), andstirred for 5 minutes. The mixture was treated with 2M Na₂CO₃ (1.5 mL,3.0 mmol), heated to 75° C., stirred for 18 hours, cooled to roomtemperature, filtered, triturated with water (3 mL), and concentrated.The concentrate was treated with boiling water (4 mL), filtered throughcelite, cooled to room temperature, adjusted to pH<7 with HCl, andfiltered to provide the desired product. MS (APCI(+)) m/e 239 (M+H)⁺.

EXAMPLE 29B4-((1-adamantylmethyl)amino)-N-(4-(2-chloro-3-thienyl)benzoyl)-3-nitrobenzenesulfonamide

A room temperature mixture of Example 29A (39.4 mg, 0.17 mmol),resin-bound dicyclohexylcarbodiimide (225.0 mg, 1.83 mmol/g), anddimethylaminopyridine (60.0 mg, 4.95 mmol) was treated with a solutionof Example 28A (40 mg, 0.11 mmol) in a 1:1 mixture of 1,2-dichloroethaneand 2-methyl-2-propanol (3 mL), and agitated overnight on an ArgonautTechnologies Quest 210. The mixture was treated with resin bound p-TsOH(990 mg, 1.44 mmol/g), agitated for 1 hour, decanted, and washed withdichloromethane. The combined extracts were concentrated and purified byHPLC using 0.1% TFA in H₂O/CH₃CN to provide the desired product. MS(APCI(+)) m/e 586 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ12.50 (s, 1H), 8.66(d, 1H), 8.57 (t, 1H), 7.96 (d, 2H), 7.95 (dd, 1H), 7.71 (d, 2H), 7.59(d, 1H), 7.36 (d, 1H), 7.29 (d, 1H), 7.29 (d, 1H), 3.17 (d, 2H), 1.97(s, 3H), 1.58 (m, 12H).

EXAMPLE 304-((1-adamantylmethyl)amino)-N-((1,1′-biphenyl)-4-ylcarbonyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting(1,1′-biphenyl)carboxylic acid for Example 29A in Example 29B. MS(APCI(+)) m/e 546 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ12.46 (s, 1H), 8.68(d, 1H), 8.58 (t, 1H), 7.96 (d, 2H), 7.95 (dd, 1H), 7.80 (d, 2H), 7.73(d, 2H), 7.50 (t, 2H), 7.42 (t, 1H), 7.37 (d, 1H), 3.17 (m, 2H), 1.97(s, 3H), 1.58 (m, 12H).

EXAMPLE 314-((1-adamantylmethyl)amino)-N-((4′-methyl(1,1′-biphenyl)-4-yl)carbonyl)-3-nitrobenzenesulfonamideEXAMPLE 31A 4′-methyl(1,1′-biphenyl)-4-carboxylic acid

A room temperature solution of ethyl 4-bromobenzoate (0.70 mL, 4.3 mmol)in DME (20 mL) was treated with Pd(PPh₃)₄ (246 mg, 0.2 mmol), stirredfor 5 minutes, treated with a solution of 4-methylphenylboronic acid(870 mg, 6.4 mmol) in ethanol (10 mL), stirred for 5 minutes, treatedwith 2M Na₂CO₃ (18.0 mL, 36.0 mmol), heated to reflux, stirred for 16hours, and concentrated. The concentrate was dissolved in water (75 mL)and diethyl ether (50 mL), filtered through celite, and extracted withdiethyl ether. The combined extracts were washed with brine, dried(MgSO₄), filtered, and concentrated. The concentrate was purified byflash column chromatography on silica gel with 33% acetone/hexanes. Theresulting product was dissolved in methanol (10 mL) and THF (5 mL),treated with 1M NaOH (4.3 mL, 4.3 mmol), stirred for 48 hours,concentrated, dissolved in water (10 mL), adjusted to pH 1 with 12M HCl,and filtered. Recrystallization from ethyl acetate provided the desiredproduct. MS (APCI(+)) m/e 213 (M+H)⁺.

EXAMPLE 31B4-((1-adamantylmethyl)amino)-N-((4′-methyl(1,1′-biphenyl)-4-yl)carbonyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 31A for Example29A in Example 29B. MS (APCI(+)) m/e 560 (M+H)⁺; ¹H NMR (500 MHz,DMSO-d₆) δ12.44 (s, 1H), 8.67 (d, 1H), 8.57 (t, 1H), 7.95 (dd, 1H), 7.94(d, 2H), 7.77 (d, 2H), 7.63 (d, 2H), 7.36 (d, 1H), 7.30 (d, 2H), 3.17(d, 2H), 2.35 (s, 3H), 1.97 (s, 3H), 1.58 (m, 12H).

EXAMPLE 324-((1-adamantylmethyl)amino)-N-((4′-ethyl(1,1′-biphenyl)-4-yl)carbonyl)-3-nitrobenzenesulfonamideEXAMPLE 32A 4′-ethyl(1,1′-biphenyl)-4-carboxylic acid

The desired product was prepared by substituting 1-bromo-4-ethylbenzenefor 2-bromo-5-chlorothiophene in Example 29A. MS (APCI(−)) m/e 225(M−H)⁻.

EXAMPLE 32B4-((1-adamantylmethyl)amino)-N-((4′-ethyl(1,1′-biphenyl)-4-yl)carbonyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 32A for Example29A in Example 29B. MS (APCI(+)) m/e 574 (M+H)⁺; ¹H NMR (500 MHz,DMSO-d₆) δ12.45 (s, 1H), 8.67 (d, 1H), 8.57 (t, 1H), 7.95 (dd, 1H), 7.94(d, 2H), 7.77 (d, 2H), 7.65 (d, 2H), 7.36 (d, 1H), 7.32 (d, 2H), 3.17(d, 2H), 2.65 (q, 2H), 1.97 (s, 3H), 1.58 (m, 12H), 1.20 (t, 3H).

EXAMPLE 334-((1-adamantylmethyl)amino)-3-nitro-N-((4′-propyl(1,1′-biphenyl)-4-yl)carbonyl)benzenesulfonamideEXAMPLE 33A 4′-propyl(1,1′-biphenyl)-4-carboxylic acid

The desired product was prepared by substituting 1-bromo-4-propylbenzenefor 2-bromo-5-chlorothiophene in Example 29A. MS (APCI(−)) m/e 239(M−H)⁻.

EXAMPLE 33B4-((1-adamantylmethyl)amino)-3-nitro-N-((4′-propyl(1,1′-biphenyl)-4-yl)carbonyl)benzenesulfonamide

The desired product was prepared by substituting Example 33A for Example29A in Example 29B. MS (APCI(+)) m/e 588 (M+H)⁺; ¹H NMR (500 MHz,DMSO-d₆) δ12.43 (s, 1H), 8.67 (d, 1H), 8.57 (t, 1H), 7.95 (dd, 1H), 7.94(d, 2H), 7.77 (d, 2H), 7.64 (d, 2H), 7.36 (d, 1H), 7.30 (d, 2H), 3.18(d, 2H), 2.60 (t, 2H), 1.97 (s, 3H), 1.58 (m, 14H), 0.90 (t, 3H).

EXAMPLE 344-((1-adamantylmethyl)amino)-N-((3′-chloro(1,1′-biphenyl)-4-yl)carbonyl)-3-nitrobenzenesulfonamideEXAMPLE 34A 3′-chloro-1,1′-biphenyl-4-carboxylic acid

The desired product was prepared by substituting 3-chlorophenylboronicacid for 4-methylphenylboronic acid in Example 31A.

EXAMPLE 34B4-((1-adamantylmethyl)amino)-N-((3′-chloro(1,1′-biphenyl)-4-yl)carbonyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 34A for Example29A in Example 29B. MS (APCI(+)) m/e 580 (M+H)⁺; ¹H NMR (500 MHz,DMSO-d₆) δ8.67 (d, 1H), 8.57 (t, 1H), 8.57 (t, 1H), 7.96 (d, 2H), 7.95(d, 1H), 7.83 (d, 2H), 7.80 (t, 1H), 7.70 (dt, 1H), 7.50 (m, 2H), 7.36(d, 1H), 3.18 (m, 2H), 1.97 (s, 3H), 1.58 (m, 12H).

EXAMPLE 35N-((3′-acetyl(1,1′-biphenyl)-4-yl)carbonyl)-4-((1-adamantylmethyl)amino)-3-nitrobenzenesulfonamideEXAMPLE 35A 3′-acetyl(1,1′-biphenyl)-4-carboxylic acid

The desired product was prepared by substituting1-(3-bromophenyl)ethanone for 2-bromo-5-chlorothiophene in Example 29A.MS (APCI(−)) m/e 239 (M−H)⁻.

EXAMPLE 35BN-((3′-acetyl(1,1′-biphenyl)-4-yl)carbonyl)-4-((1-adamantylmethyl)amino)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 35A for Example29A in Example 29B. MS (APCI(+)) m/e 588 (M+H)⁺; ¹H NMR (500 MHz,DMSO-d₆) δ8.68 (d, 1H), 8.57 (t, 1H), 8.24 (t, 1H), 7.99 (d, 4H), 7.95(dd, 1H), 7.88 (d, 2H), 7.64 (t, 1H), 7.36 (d, 1H),), 3.17 (m, 2H), 2.66(s, 3H), 1.97 (s, 3H), 1.58 (m, 12H).

EXAMPLE 364-((1-adamantylmethyl)amino)-N-((4′-chloro(1,1′-biphenyl)-4-yl)carbonyl)-3-nitrobenzenesulfonamideEXAMPLE 36A 4′-chloro(1,1′-biphenyl)-4-carboxylic acid

The desired product was prepared by substituting 4-chlorophenylboronicacid for 4-methylphenylboronic acid in Example 31A. MS (APCI(−)) m/e 231(M−H)⁻.

EXAMPLE 36B4-((1-adamantylmethyl)amino)-N-((4′-chloro(1,1′-biphenyl)-4-yl)carbonyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 36A for Example29A in Example 29B. MS (APCI(+)) m/e 580 (M+H)⁺; ¹H NMR (500 MHz,DMSO-d₆) δ8.67 (d, 1H), 8.57 (t, 1H), 7.95 (m, 3H), 7.80 (d, 2H), 7.77(d, 2H), 7.54 (d, 2H), 7.36 (d, 1H), 3.17 (d, 2H), 2.66 (s, 3H), 1.97(s, 3H), 1.58 (m, 12H).

EXAMPLE 374-((1-adamantylmethy)amino)-N-((3′,4′-dichloro(1,1′-biphenyl)-4-yl)carbonyl)-3-nitrobenzenesulfonamideEXAMPLE 37A 3′,4′-dichloro(1,1′-biphenyl)-4-carboxylic acid

The desired product was prepared by substituting4-bromo-1,2-dichlorobenzene for 2-bromo-5-chlorothiophene in Example29A. MS (APCI(−)) m/e 265 (M−H)⁺.

EXAMPLE 37B4-((1-adamantylmethyl)amino)-N-((3′,4′-dichloro(1,1′-biphenyl)-4-yl)carbonyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 37A for Example29A in Example 29B. MS (APCI(+)) m/e 614 (M+H)⁺; ¹H NMR (500 MHz,DMSO-d₆) δ8.67 (d, 1H), 8.57 (t, 1H), 7.94 (m, 3H), 7.85 (d, 2H), 7.74(m, 2H), 7.36 (d, 1H), 3.17 (d, 2H), 1.97 (s, 3H), 1.58 (m, 12H).

EXAMPLE 384-((1-adamantylmethyl)amino)-N-((4′-methoxy(1,1′-biphenyl)-4-yl)carbonyl)-3-nitrobenzenesulfonamideEXAMPLE 38A 4′-methoxy(1,1′-biphenyl)-4-carboxylic acid

The desired product was prepared by substituting1-bromo-4-methoxybenzene for 2-bromo-5-chlorothiophene in Example 29A.MS (APCI(−)) m/e 227 (M−H)⁻.

EXAMPLE 38B4-((1-adamantylmethyl)amino)-N-((4′-methoxy(1,1′-biphenyl)-4-yl)carbonyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 38A for Example29A in Example 29B. MS (APCI(+)) m/e 576 (M+H)⁺; ¹H NMR (500 MHz,DMSO-d₆) δ8.67 (d, 1H), 8.57 (t, 1H), 7.94 (dd, 1H), 7.92 (d, 2H), 7.74(d, 2H), 7.69 (d, 2H), 7.36 (d, 1H), 7.00 (d, 2H), 3.80 (s, 3H), 3.18(d, 2H), 1.97 (s, 3H), 1.58 (m, 12H).

EXAMPLE 394-((1-adamantylmethyl)amino)-N-((4′-fluoro(1,1′-biphenyl)-4-yl)carbonyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting 1-adamantanemethylaminefor 2,2-dimethylcyclopentylamine in Example 1E. MS (APCI(+)) m/e 581(M+NH₄)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ12.45 (br s, 1H), 8.67 (d, 1H),8.57 (t, 1H), 7.95 (m, 3H), 7.78 (2d, 4H), 7.36 (d, 1H), 7.32 (t, 2H),3.18 (d, 2H), 1.97 (s, 3H), 1.70-1.60 (m, 12H).

EXAMPLE 40N-((4′-acetyl(1,1′-biphenyl)-4-yl)carbonyl)-4-((1-adamantylmethyl)amino)-3-nitrobenzenesulfonamideEXAMPLE 40A 4′-acetyl(1,1′-biphenyl)-4-carboxylic acid

The desired product was prepared by substituting1-(4-bromophenyl)ethanone for 2-bromo-5-chlorothiophene in Example 29A.MS (APCI(−)) m/e 239 (M−H)⁻.

EXAMPLE 40BN-((4′-acetyl(1,1′-biphenyl)-4-yl)carbonyl)-4-((1-adamantylmethyl)amino)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 40A for Example29A in Example 29B. MS (APCI(+)) m/e 588 (M+H)⁺; ¹H NMR (500 MHz,DMSO-d₆) δ8.67 (d, 1H), 8.57 (t, 1H), 8.05 (d, 2H), 7.99 (d, 2H), 7.95(dd, 1H), 7.88 (t, 4H), 7.36 (d, 1H), 3.18 (m, 2H), 2.60 (s, 3H), 1.97(s, 3H), 1.58 (m, 12H).

EXAMPLE 414-((1-adamantylmethyl)amino)-N-((2′,3′-dimethyl(1,1′-biphenyl)-4-yl)carbonyl)-3-nitrobenzenesulfonamideEXAMPLE 41A 2′,3′-dimethyl(1,1′-biphenyl)-4-carboxylic acid

The desired product was prepared by substituting1-bromo-2,3-dimethylbenzene for 2-bromo-5-chlorothiophene in Example29A. MS (APCI(−)) m/e 225 (M−H)⁻.

EXAMPLE 41B4-((1-adamantylmethyl)amino)-N-((2′,3′-dimethyl(1,1′-biphenyl)-4-yl)carbonyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 41A for Example29A in Example 29B. MS (APCI(+)) m/e 574 (M+H)⁺; ¹H NMR (300 MHz,DMSO-d₆) δ8.62 (d, 1H), 8.56 (m, 1H), 7.89 (m, 3H), 7.36 (m, 3H), 7.15(m, 2H), 6.96 (d, 1H), 3.14 (d, 2H), 2.25 (s, 3H), 2.03 (s, 3H), 1.92(s, 3H), 1.58 (m, 12H).

EXAMPLE 424-((1-adamantylmethyl)amino)-N-((4′-fluoro-2′-nitro(1,1′-biphenyl)-4-yl)carbonyl)-3-nitrobenzenesulfonamideEXAMPLE 42A methyl 4′-fluoro-2′-nitro(1,1′-biphenyl)-4-carboxylate

The desired product was prepared by substituting1-bromo-4-fluoro-2-nitrobenzene for Example 5A in Example 5B. MS (DCI)m/e 276 (M+H)⁺.

EXAMPLE 42B4-((1-adamantylmethyl)amino)-N-((4′-fluoro-2′-nitro(1,1′-biphenyl)-4-yl)carbonyl)-3-nitrobenzenesulfonamide

The procedure used in Example 5 was used here to convert the productsfrom Examples 42A and 28A to the title compound. MS (ESI(−)) m/e 607(M−H)⁻; ¹H NMR (400 MHz, DMSO-d₆) δ8.67 (d, 1H), 8.58 (t, 1H), 8.07 (dd,1H), 7.94 (m, 3H), 7.71 (dt, 1H), 7.63 (d, 1H), 7.46 (d, 2H), 7.36 (d,1H), 3.18 (d, 2H), 1.99 (m, 3H), 1.75-1.50 (m, 12H).

EXAMPLE 434-((1-adamantylmethyl)amino)-N-((2′-amino-4′-fluoro(1,1′-biphenyl)-4-yl)carbonyl)-3-nitrobenzenesulfonamideEXAMPLE 43A methyl 2′-amino-4′-fluoro(1,1′-biphenyl)-4-carboxylate

The desired product was prepared by substituting Example 42A for Example5B in Example 5C. MS (DCI) m/e 246 (M+H)⁺.

EXAMPLE 43B4-((1-adamantylmethyl)amino)-N-((2′-amino-4′-fluoro(1,1′-biphenyl)-4-yl)carbonyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 43A and Example28A for Example 5C and Example 3A, respectively, in Example 5D. MS(ESI(−)) m/e 577 (M−H)⁻; ¹H NMR (400 MHz, DMSO-d₆) δ8.60 (t, 1H), 7.94(m, 3H), 7.50 (d, 2H), 7.38 (d, 1H), 7.00 (dd, 1H), 6.55 (dd, 1H), 6.42(dt, 1H), 5.22 (br s, 2H), 3.17 (d, 2H), 1.98 (m, 3H), 1.72-1.55 (m,12H).

EXAMPLE 444-((1-adamantylmethyl)amino)-N-((4′-fluoro-2′-(methylamino)(1,1′-biphenyl)-4-yl)carbonyl)-3-nitrobenzenesulfonamideEXAMPLES 44A and 44B methyl4′-fluoro-2′-(methylamino)(1,1′-biphenyl)-4-carboxylate and methyl2′-(dimethylamino)-4′-fluoro(1,1′-biphenyl)-4-carboxylate

A room temperature suspension of sodium hydride (31 mg, 1.3 mmol) in THF(2 mL) was treated sequentially with a solution of Example 44A (123 mg,0.50 mmol) in THF (2 mL) and methyl iodide (144 mg, 1.0 mmol), stirredfor 1 hour, diluted with ethyl acetate (50 mL). washed sequentially with1M HCl (5 mL), water (5 mL), and brine (5 mL), dried (MgSO₄), filtered,and concentrated. The concentrate was purified by flash columnchromatography on silica gel with 70:25:51/hexanes:dichloromethane:ethylacetate to provide the desired products.

EXAMPLE 44C4-((1-adamantylmethyl)amino)-N-((4′-fluoro-2′-(methylamino)(1,1′-biphenyl)-4-yl)carbonyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 44A and Example28A for Example 5C and Example 3A, respectively, in Example 5D. MS(ESI(−)) m/e 591 (M−H)⁻; ¹H NMR (400 MHz, DMSO-d₆) δ8.67 (d, 1H), 8.57(t, 1H), 7.94 (m, 3H), 7.45 (d, 2H), 7.36 (d, 1H), 6.97 (dd, 1H), 6.40(m, 2H), 5.19 (br s, 1H), 3.18 (d, 2H), 2.63 (d, 3H), 1.98 (m, 3H),1.72-1.55 (m, 12H).

EXAMPLE 454-((1-adamantylmethyl)amino)-N-((2′-(dimethylamino)-4′-fluoro(1,1′-biphenyl)-4-yl)carbonyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 44B and Example28A for Example 5C and Example 3A, respectively, in Example 5D. MS(ESI(−)) m/e 605 (M−H)⁻; ¹H NMR (400 MHz, DMSO-d₆) δ8.60 (d, 1H), 8.50(t, 1H), 7.92 (m, 3H), 7.52 (m, 2H), 7.28 (m, 1H), 7.18 (dd, 1H), 6.81(m, 2H), 3.17 (d, 2H), 2.46 (s, 6H), 1.98 (m, 3H), 1.72-1.55 (m, 12H).

EXAMPLE 464-((((4-((1-adamantylmethyl)amino)-3-nitrophenyl)sulfonyl)amino)carbonyl)-4′-fluoro-2′-((methoxycarbonyl)amino)-1,1′-biphenyl

A room temperature solution of Example 43B (30 mg, 0.051 mmol), methylchloroformate (0.05 mL, 0.65 mmol), N,N-diisopropylethylamine (0.1 mL,0.57 mmol) and DMAP (3 mg, 0.02 mmol) in dichloromethane (1 mL) wasstirred for 16 hours, treated with 4M HCl (0.3 mL), and concentrated.The concentrate was purified by flash column chromatography on silicagel with 50-100% ethyl acetate/hexanes to provide the desired product.MS (ESI(−)) m/e 635 (M−H)⁻; ¹H NMR (400 MHz, DMSO-d₆) δ8.89 (br s, 1H),8.65 (d, 1H), 8.56 (t, 1H), 7.92 (m, 3H), 7.43 (d, 2H), 7.35 (m, 3H),7.12 (dt, 1H), 3.50 (s, 3H), 3.18 (d, 2H), 1.98 (m, 3H), 1.72-1.55 (m,12H).

EXAMPLE 474-((1-adamantylmethyl)amino)-N-((2′-(((dimethylamino)carbonyl)amino)-4′-fluoro(1,1′-biphenyl)-4-yl)carbonyl)-3-nitrobenzenesulfonamideEXAMPLE 47A methyl2′-(((dimethylamino)carbonyl)amino)-4′-fluoro(1,1′-biphenyl)-4-carboxylate

A room temperature solution of Example 43A (100 mg, 0.41 mmol) indichloromethane (2 mL) was treated with 1.9M phosgene in toluene (0.26mL) and N,N-diisopropylethylamine (0.2 mL, 1.2 mmol), stirred for 16hours, treated with 2M dimethylamine in THF (0.5 mL), stirred for 1hour, and concentrated. The concentrate was purified by flash columnchromatography on silica gel with 50% ethyl acetate/hexanes to providethe desired product.

EXAMPLE 47B4-((1-adamantylmethyl)amino)-N-((2′-(((dimethylamino)carbonyl)amino)-4′-fluoro(1,1′-biphenyl)-4-yl)carbonyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 47A and Example28A for Example 5C and Example 3A, respectively, in Example 5D. MS(ESI(+)) m/e 650 (M+H)⁺; ¹H NMR (400 MHz, DMSO-d₆) δ8.67 (d, 1H), 8.59(t, 1H), 7.95 (dd, 1H), 7.91 (d, 2H), 7.78 (s, 1H), 7.50 (d, 2H) 7.42(dd, 1H), 7.37 (d, 1H), 7.31 (dd, 1H), 7.05 (dt, 1H), 3.18 (d, 2H), 2.75(s, 6H), 1.98 (m, 3H), 1.72-1.55 (m, 12H).

EXAMPLE 48N-(4′-((((4-((1-adamantylmethyl)amino)-3-nitrophenyl)sulfonyl)amino)carbonyl)-4-fluoro(1,1′-biphenyl)-2-yl)-4-morpholinecarboxamide

The desired product was prepared by substituting morpholine fordimethylamine in Example 47. MS (ESI(−)) m/e 690 (M−H)⁻; ¹H NMR (400MHz, DMSO-d₆) δ8.66 (d, 1H), 8.57 (t, 1H), 8.20 (br s, 1H), 7.92 (m,3H), 7.46 (d, 2H), 7.47-7.24 (m, 4H), 7.08 (dt, 1H), 3.47 (m, 4H), 3.24(m, 4H), 3.18 (d, 2H), 1.98 (m, 3H), 1.72-1.55 (m, 12H).

EXAMPLE 49N-(4′-((((4-((1-adamantylmethyl)amino)-3-nitrophenyl)sulfonyl)amino)carbonyl)-4-fluoro(1,1′-biphenyl)-2-yl)-3-aminopropanamideEXAMPLE 49A4-((((4-((1-adamantylmethyl)amino)-3-nitrophenyl)sulfonyl)amino)carbonyl)-2′-((3-((tert-butoxycarbonyl)amino)propanoyl)amino)-4′-fluoro-1,1′-biphenyl

A room temperature solution of Example 43 (25 mg, 0.04 mmol),N-(tert-butoxycarbonyl)-β-alanine (25 mg, 0.13 mmol), EDCI (38 mg, 0.20mmol), and DMAP (2 mg, 0.02 mmol) in dichloromethane (2 mL) was stirredfor 16 hours, diluted with ethyl acetate (50 mL), washed sequentiallywith 1M HCl (5 mL), water (5 mL), and brine (5 mL), dried (MgSO₄),filtered, and concentrated. The concentrate was purified by flash columnchromatography on silica gel with 2-8% methanol/dichloromethane toprovide the desired product. MS (ESI(−)) m/e 748 (M−H)⁻.

EXAMPLE 49BN-(4′-((((4-((1-adamantylmethyl)amino)-3-nitrophenyl)sulfonyl)amino)carbonyl)-4-fluoro(1,1′-biphenyl)-2-yl)-3-aminopropanamide

A room temperature solution of Example 49A (19 mg, 0.03 mmol) indichloromethane (1 mL) was treated with 4M HCl in dioxane, stirred for 4hours, and concentrated to provide the desired product. MS (ESI(+)) m/e650 (M+H)⁺; ¹H NMR (400 MHz, DMSO-d₆) δ9.12 (br s, 1H), 8.65 (d, 1H),8.56 (t, 1H), 7.95 (dd, 1H), 7.94 (m, 3H), 7.65 (br s, 3H), 7.50-7.35(m, 4H), 7.15 (dt, 1H), 3.18 (d, 2H), 2.75 (s, 6H), 1.98 (m, 3H),1.72-1.55 (m, 12H).

EXAMPLE 504-((1-adamantylmethyl)amino)-3-nitro-N-((2′,4′,5′-trimethyl(1,1′-biphenyl)-4-yl)carbonyl)benzenesulfonamideEXAMPLE 50A 2′,4′,5′-trimethyl(1,1′-biphenyl)-4-carboxylic acid

The desired product was prepared by substituting1-bromo-2,4,5-trimethylbenzene for 2-bromo-5-chlorothiophene in Example29A. MS (APCI(−)) m/e 239 (M−H)⁻.

EXAMPLE 50B4-((1-adamantylmethyl)amino)-3-nitro-N-((2′,4′,5′-trimethyl(1,1′-biphenyl)-4-yl)carbonyl)benzenesulfonamide

The desired product was prepared by substituting Example 50A for Example29A in Example 29B. MS (APCI(+) m/e 588 (M+H)⁺; ¹H NMR (500 MHz,DMSO-d₆) δ8.67 (d, 1H), 8.57 (t, 1H), 7.95 (dd, 1H), 7.91 (d, 2H), 7.41(d, 2H), 7.36 (d, 1H), 7.06 (s, 1H), 6.97 (s, 1H), 3.18 (d, 2H), 2.21(s, 3H), 2.20 (s, 3H), 2.13 (s, 3H), 1.97 (s, 3H), 1.58 (m, 12H).

EXAMPLE 514-((1-adamantylmethyl)amino)-N-(4-mesitylbenzoyl)-3-nitrobenzenesulfonamideEXAMPLE 51A 2′,4′,6′-trimethyl(1,1′-biphenyl)-4-carboxylic acid

The desired product was prepared by substituting2-bromo-1,3,5-trimethylbenzene for 2-bromo-5-chlorothiophene in Example29A. MS (APCI(−)) m/e 239 (M−H)⁻.

EXAMPLE 51B4-((1-adamantylmethyl)amino)-N-(4-mesitylbenzoyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 51A for Example29A in Example 29B. MS (APCI(+)) m/e 588 (M+H)⁺; ¹H NMR (500 MHz,DMSO-d₆) δ8.67 (d, 1H), 8.57 (t, 1H), 7.95 (m, 3H), 7.36 (d, 1H), 7.23(d, 2H), 6.93 (s, 2H), 3.18 (d, 2H), 2.26 (s, 3H), 1.97 (s, 3H), 1.89(s, 6H), 1.58 (m, 12H).

EXAMPLE 524-((1-adamantylmethyl)amino)-N-(4-(1,3-benzodioxol-5-yl)benzoyl)-3-nitrobenzenesulfonamideEXAMPLE 52A 4-(1,3-benzodioxol-5-yl)benzoic acid

The desired product was prepared by substituting5-bromo-1,3-benzodioxole for 2-bromo-5-chlorothiophene in Example 29A.

EXAMPLE 52B4-((1-adamantylmethyl)amino)-N-(4-(1,3-benzodioxol-5-yl)benzoyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 52A for Example29A in Example 29B. MS (APCI(+)) m/e 590 (M+H)⁺; ¹H NMR (500 MHz,DMSO-d₆) δ8.66 (d, 1H), 8.57 (t, 1H), 7.95 (dd, 1H), 7.91 (d, 2H), 7.73(d, 2H), 7.36 (d, 1H), 7.33 (d, 1H), 7.24 (dd, 1H), 7.01 (d, 1H), 6.08(s, 2H), 3.18 (d, 2H), 1.97 (s, 3H), 1.58 (m, 12H).

EXAMPLE 534-((1-adamantylmethyl)amino)-N-(4-(1H-indol-6-yl)benzoyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 4A and Example28A for Example 1B and Example 1C, respectively, in Example 1D. MS(ESI(−)) m/e 583 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ8.65 (m, 1H), 8.55(m, 1H), 7.97 (m, 2H), 7.77 (m, 2H), 7.67 (m, 2H), 7.38 (m, 3H), 6.48(m, 1H), 3.18 (m, 2H), 1.98 (m, 3H), 1.62 (m, 12H).

EXAMPLE 544-((1-adamantylmethyl)amino)-N-(4-(2-methyl-1,3-benzoxazol-5-yl)benzoyl)-3-nitrobenzenesulfonamideEXAMPLE 54A methyl 4-(2-methyl-1,3-benzoxazol-5-yl)benzoate

A room temperature solution of 5-chloro-2-methyl-1,3-benzoxazole (110mg, 0.71 mmol), CsF (325 mg, 2.14 mmol), Pd(OAc)₂ (6.0 mg, 0.028 mmol),2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (14 mg, 0.036mmol) and 4-(methoxycarbonyl)phenylboronic acid (180 mg, 1.0 mmol) indioxane (4 mL) was stirred for 18 hours and concentrated. Theconcentrate was purified by flash column chromatography on silica gelwith 15% ethyl acetate/hexanes to provide the desired product. ¹H NMR(300 MHz, DMSO-d₆) δ8.06 (d, 2H), 8.03 (d, 1H), 7.90 (d, 2H), 7.78 (d,2H), 7.71 (dd, 1H), 7.29 (d, 2H), 3.90 (s, 3H), 2.65 (s, 3H).

EXAMPLE 54B 4-(2-methyl-1,3-benzoxazol-5-yl)benzoic acid

A room temperature solution of Example 54A (80 mg, 3.0 mmol) and LiOH(630 mg, 15.0 mmol) in a mixture of THF (15 mL), water (4 mL), andmethanol (4 mL) was stirred for 1 hour, poured into 1M HCl, andextracted with ethyl acetate. The combined extracts were washed withbrine, dried (Na₂SO₄), filtered, and concentrated to provide the desiredproduct of sufficient purity for subsequent use.

EXAMPLE 54C4-((1-adamantylmethyl)amino)-N-(4-(2-methyl-1,3-benzoxazol-5-yl)benzoyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 54B and Example28A for Example 1B and Example 1C, respectively, in Example 1D. MS(ESI(−)) m/e 599 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ8.52 (d, 1H),7.99-7.92 (m, 3H), 7.90 (dd, 1H), 7.64-7.52 (m, 4H), 7.17(d, 1H), 3.12(d, 2H), 2.63 (s, 3H), 1.97 (m, 2H), 1.71-1.54 (m, 13H).

EXAMPLE 554-((1-adamantylmethyl)amino)-N-(4-(2-methyl-1,3-benzothiazol-5-yl)benzoyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 17A and Example28A for Example 1B and Example 1C, respectively, in Example 1D. MS(ESI(−)) m/e 615 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ8.68 (d, 1H), 8.59(t, 1H), 8.26 (s, 1H), 8.14 (d, 1H), 7.98 (d, 2H), 7.95 (dd, 1H), 7.90(d, 2H), 7.77 (dd, 1H), 7.37 (d, 1H), 3.19 (d, 2H), 2.82 (s, 3H), 1.98(br s, 3H), 1.73-1.55 (m, 12H).

EXAMPLE 564-((1-adamantylmethyl)amino)-N-(4-(2-ethyl-1,3-benzothiazol-5-yl)benzoyl)-3-nitrobenzenesulfonamideEXAMPLE 56A 5-bromo-2-ethyl-1,3-benzothiazole

A 0° C. solution of diisopropylamine (340 μL, 2.41 mmol) in THF (3 mL)was treated with 2.5M n-butyllithium in hexanes (0.88 mL), stirred for20 minutes, added to a −78° C. solution of5-bromo-2-methyl-1,3-benzothiazole (250 mg, 1.10 mmol) in THF (3 mL),stirred for 30 minutes, treated with iodomethane (340 μL, 5.50 mmol),and stirred for 1 hour. The mixture was diluted with ethyl acetate (50mL), washed sequentially with 1M HCl (5 mL), water (5 mL), and brine (5mL), dried (MgSO₄), filtered, and concentrated. The concentrate waspurified by flash column chromatography on silica gel with 30%hexanes/dichloromethane to provide the desired product. MS (DCI) m/e 242(M+H)⁺.

EXAMPLE 56B 4-(2-ethyl-1,3-benzothiazol-5-yl)benzoic acid

The desired product was prepared by substituting Example 56A for6-bromoindole in Example 4A. MS (ESI(+)) m/e 284 (M+H)⁺.

EXAMPLE 56C4-((1-adamantylmethyl)amino)-N-(4-(2-ethyl-1,3-benzothiazol-5-yl)benzoyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 56 B andExample 28A for Example 1B and Example 1C, respectively, in Example 1D.MS (ESI(−)) m/e 629(M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ8.68 (d, 1H), 8.57(t, 1H), 8.28 (s, 1H), 8.16 (d, 1H), 7.98 (d, 2H), 7.95 (dd, 1H), 7.90(d, 2H), 7.77 (dd, 1H), 7.36 (d, 1H), 3.19 (d, 2H), 3.15 (q, 2H), 1.98(br s, 3H), 1.73-1.55 (m, 12H), 1.40 (t, 3H).

EXAMPLE 57N-(4-(3,4,4a,5,6,7,8,8a-octahydro-1-naphthalenyl)benzoyl)-4-((1-adamantylmethyl)amino)-3-nitrobenzenesulfonamideand4-((1-adamantylmethyl)amino)-N-(4-(2,3,4,4a,5,6,7,8-octahydro-1-naphthalenyl)benzoyl)-3-nitrobenzenesulfonamideEXAMPLE 57A methyl4-(3,4,4a,5,6,7,8,8a-octahydro-1-naphthalenyl)benzoate and methyl4-(2,3,4,4a,5,6,7,8-octahydro-1-naphthalenyl)benzoate

The desired product was prepared by substituting 1-decalone for4-tert-butylcyclohexanone in Examples 5A and 5B. MS (DCI) m/e 271(M+H)⁺.

EXAMPLE 57BN-(4-(3,4,4a,5,6,7,8,8a-octahydro-1-naphthalenyl)benzoyl)-4-((1-adamantylmethyl)amino)-3-nitrobenzenesulfonamideand4-((1-adamantylmethyl)amino)-N-(4-(2,3,4,4a,5,6,7,8-octahydro-1-naphthalenyl)benzoyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 57A and Example28A for Example 5C and Example 3A, respectively, in Example 5D. MS(ESI(+)) m/e 604 (M+H)⁺; ¹H NMR (400 MHz, DMSO-d₆) δ8.64 (d, 1H), 8.59(t, 1H), 7.92 (dd, 1H), 7.80 (d, 2H), 7.36 (d, 1H), 7.28 (d, 2H), 5.80(m, 1H), 3.18 (d, 2H), 2.30-2.20 (m, 3H), 1.96 (m, 3H), 1.70-1.55 (m,17H), 1.40-1.20 (m, 6H).

EXAMPLE 58N-(4-(1,4,4a,5,6,7,8,8a-octahydro-2-naphthalenyl)benzoyl)-4-((1-adamantylmethyl)amino)-3-nitrobenzenesulfonamideandN-(4-(3,4,4a,5,6,7,8,8a-octahydro-2-naphthalenyl)benzoyl)-4-((1-adamantylmethyl)amino)-3-nitrobenzenesulfonamideEXAMPLE 58A methyl4-(1,4,4a,5,6,7,8,8a-octahydro-2-naphthalenyl)benzoate and methyl4-(3,4,4a,5,6,7,8,8a-octahydro-2-naphthalenyl)benzoate

The desired product was prepared by substituting 2-decalone for4-tert-butylcyclohexanone in Examples 5A and 5B. MS (DCI) m/e 271(M+H)⁺.

EXAMPLE 58BN-(4-(1,4,4a,5,6,7,8,8a-octahydro-2-naphthalenyl)benzoyl)-4-((1-adamantylmethyl)amino)-3-nitrobenzenesulfonamideandN-(4-(3,4,4a5,6,7,8,8a-octahydro-2-naphthalenyl)benzoyl)-4-((1-adamantylmethyl)amino)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 58A and Example28A for Example 5C and Example 3A, respectively, in Example 5D. MS(ESI(+)) m/e 604 (M+H)⁺; ¹H NMR (400 MHz, DMSO-d₆) δ8.52 (d, 1H), 8.40(t, 1H), 7.88 (dd, 1H), 7.80 (d, 2H), 7.36 (d, 2H), 7.28 (d, 2H), 6.13and 6.07 (m, 1H total), 3.12 (d, 2H), 2.38 (m, 3H), 1.96 (m, 3H),1.70-1.40 (m, 23H).

EXAMPLE 594-((1-adamantylmethyl)amino)-N-(4-decahydro-1-naphthalenylbenzoyl)-3-nitrobenzenesulfonamideEXAMPLE 59A methyl 4-decahydro-1-naphthalenylbenzoate

The desired product was prepared by substituting Example 57A for Example5B in Example 5C. MS (DCI) m/e 273 (M+H)⁺.

EXAMPLE 59B4-((1-adamantylmethyl)amino)-N-(4-decahydro-1-naphthalenylbenzoyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 59A and Example28A for Example 5C and Example 3A, respectively, in Example 5D. MS(ESI(+)) m/e 606 (M+H)⁺; ¹H NMR (400 MHz, DMSO-d₆) δ8.64 (d, 1H), 8.59(t, 1H), 7.92 (dd, 1H), 7.78 (d, 2H), 7.36 (d, 1H), 7.28 (d, 2H), 3.18(d, 2H), 2.30 (m, 1H), 1.96 (m, 3H), 1.75-1.10 (m, 28H).

EXAMPLE 604-((1-adamantylmethyl)amino)-N-(4-decahydro-2-naphthalenylbenzoyl)-3-nitrobenzenesulfonamideEXAMPLE 60A methyl 4-decahydro-2-naphthalenylbenzoate

The desired product was prepared by substituting Example 58A for Example5B in Example 5C. MS (DCI) m/e 273 (M+H)⁺.

EXAMPLE 60B4-((1-adamantylmethyl)amino)-N-(4-decahydro-2-naphthalenylbenzoyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 60A and Example28A for Example 5C and Example 3A, respectively, in Example 5D. MS (ESI)m/e 606 (M+H)⁺; ¹H NMR (400 MHz, DMSO-d₆) δ8.62 (d, 1H), 8.55 (t, 1H),7.92 (dd, 1H), 7.78 (d, 2H), 7.36 (m, 4H), 3.18 (d, 2H), 2.55 (m, 1H),1.96 (m, 3H), 1.75-1.20 (m, 28H).

EXAMPLE 614-((1-adamantylmethyl)amino)-3-nitro-N-(4-(3,5,5,8,8-pentamethyldecahydro-2-naphthalenyl)benzoyl)benzenesulfonamideEXAMPLE 61A methyl4-(3,5,5,8,8-pentamethyldecahydro-2-naphthalenyl)benzoate

The desired product was prepared by substituting3,5,5,8,8-pentamethyloctahydro-2(1H)-naphthalenone for4-tert-butylcyclohexanone in Examples 5A-5C. MS (DCI) m/e 343 (M+H)⁺.

EXAMPLE 61B4-((1-adamantylmethyl)amino)-3-nitro-N-(4-(3,5,5,8,8-pentamethyldecahydro-2-naphthalenyl)benzoyl)benzenesulfonamide

The desired product was prepared by substituting Example 61A and Example28A for Example 5C and Example 3A, respectively, in Example 5D. MS(ESI(+)) m/e 676 (M+H)⁺; ¹H NMR (400 MHz, DMSO-d₆) δ8.62 (d, 1H), 8.55(t, 1H), 7.92 (dd, 1H), 7.78 (d, 2H), 7.36 (m, 4H), 3.18 (d, 2H), 2.49(m, 1H), 1.96 (m, 3H), 1.80-1.20 (m, 22H), 0.90 (m, 6H), 0.87 (s, 3H),0.78 (s, 3H), 0.71 (s, 3H).

EXAMPLE 624-((1-adamantylmethyl)amino)-N-(4-(1-cyclohexen-1-yl)benzoyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 9A and Example28A for Example 5C and Example 3A, respectively, in Example 5D. MS(ESI(−)) m/e 548 (M−H)⁻; ¹H NMR (400 MHz, CD₃OD) δ8.86 (d, 1H), 8.03(dd, 1H), 7.76 (dt, 2H), 7.47 (dt, 2H), 7.21 (d, 1H), 6.27 (m, 1H), 3.14(t, 2H), 2.42 (m, 2H), 2.24 (m, 2H), 2.01 (m, 3H), 1.85-1.65 (m, 16H).

EXAMPLE 634-((1-adamantylmethyl)amino)-N-(4-(1-cyclohepten-1-yl)benzoyl)-3-nitrobenzenesulfonamideEXAMPLE 63A methyl 4-(1-cyclohepten-1-yl)benzoate

The desired product was prepared by substituting cycloheptanone for4-tert-butylcyclohexanone in Examples 5A and 5B. MS (DCI) m/e 231(M+H)⁺.

EXAMPLE 63B4-((1-adamantylmethyl)amino)-N-(4-(1-cyclohepten-1-yl)benzoyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 63A and Example28A for Example 5C and Example 3A, respectively, in Example 5D. MS(ESI(+)) m/e 564 (M+H)⁺; ¹H NMR (400 MHz, DMSO-d₆) δ8.63 (d, 1H),8.45(t, 1H), 7.92 (dd, 1H), 7.80 (d, 2H), 7.40 (d, 2H), 7.35 (d, 1H),6.21 (t, 1H), 3.18 (d, 2H), 2.55 (m, 2H), 2.29 (m, 2H), 1.98 (m, 3H),1.80-1.20 (m, 18H).

EXAMPLE 644-((1-adamantylmethyl)amino)-N-(4-cycloheptylbenzoyl)-3-nitrobenzenesulfonamideEXAMPLE 64A methyl 4-cycloheptylbenzoate

The desired product was prepared by substituting Example 63A for Example5B in Example 5C. MS (DCI) m/e 233 (M+H)⁺.

EXAMPLE 64B4-((1-adamantylmethyl)amino)-N-(4-cycloheptylbenzoyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 64A and Example28A for Example 5C and Example 3A, respectively, in Example 5D. MS(ESI(+)) m/e 566 (M+H)⁺; ¹H NMR (400 MHz, DMSO-d₆) δ8.63 (d, 1H), 8.55(t, 1H), 7.92 (dd, 1H), 7.79 (d, 2H), 7.35 (d, 1H), 7.30 (d, 2H), 3.18(d, 2H), 2.73 (m, 1H), 1.98 (m, 3H), 1.80-1.50 (m, 24H).

EXAMPLE 654-((1-adamantylmethyl)amino)-N-(4-(1-cycloocten-1-yl)benzoyl)-3-nitrobenzenesulfonamideEXAMPLE 65A methyl 4-(1-cycloocten-1-yl)benzoate

The desired product was prepared by substituting cyclooctanone for4-tert-butylcyclohexanone in Examples 5A and 5B. MS (DCI) m/e 245(M+H)⁺.

EXAMPLE 65B4-((1-adamantylmethyl)amino)-N-(4-(1-cycloocten-1-yl)benzoyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 65A and Example28A for Example 5C and Example 3A, respectively, in Example 5D. MS(ESI(+)) m/e 578 (M+H)⁺; ¹H NMR (400 MHz, DMSO-d₆) δ8.63 (d, 1H),8.55(t, 1H), 7.92 (dd, 1H), 7.80 (d, 2H), 7.50 (d, 2H), 7.35 (d, 1H),6.21 (t, 1H), 3.18 (d, 2H), 2.60 (m, 2H), 2.29 (m, 2H), 1.98 (m, 3H),1.80-1.20 (m, 20H).

EXAMPLE 664-((1-adamantylmethyl)amino)-N-(4-cyclooctylbenzoyl)-3-nitrobenzenesulfonamideEXAMPLE 66A methyl 4-cyclooctylbenzoate

The desired product was prepared by substituting Example 65A for Example5B in Example 5C. MS (DCI) m/e 247 (M+H)⁺.

EXAMPLE 66B4-((1-adamantylmethyl)amino)-N-(4-cyclooctylbenzoyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 66A andExample28A for Example 5C and Example 3A, respectively, in Example 5D.MS (ESI(+)) m/e 580 (M+H)⁺; ¹H NMR (400 MHz, DMSO-d₆) δ8.63 (d, 1H),8.57 (t, 1H), 7.92 (dd, 1H), 7.78 (d, 2H), 7.35 (d, 1H), 7.31 (d, 2H),3.18 (d, 2H), 2.71 (m, 1H), 1.98 (m, 3H), 1.80-1.50 (m, 26H).

EXAMPLE 674-((1-adamantylmethyl)amino)-3-nitro-N-(4-(5-nitro-2-pyridinyl)benzoyl)benzenesulfonamideEXAMPLE 67A 4-(5-nitro-2-pyridinyl)benzoic acid

The desired product was prepared by substituting 2-bromo-5-nitropyridinefor 2-bromo-5-chlorothiophene in Example 29A. MS (APCI(−)) m/e 243(M−H)⁻.

EXAMPLE 67B4-((1-adamantylmethyl)amino)-3-nitro-N-(4-(5-nitro-2-pyridinyl)benzoyl)benzenesulfonamide

The desired product was prepared by substituting Example 67A for Example29A in Example 29B. MS (APCI(+)) m/e 592 (M+H)⁺; ¹H NMR (500 MHz,DMSO-d₆) δ8.68 (m, 2H), 8.57 (t, 1H), 8.35 (d, 1H), 8.30 (d, 2H), 8.04(d, 2H), 7.96 (m, 1H), 7.36 (m, 2H), 3.18 (d, 2H), 1.97 (s, 3H), 1.58(m, 12H).

EXAMPLE 684-((1-adamantylmethy)(2-(phenylsulfanyl)ethyl)amino)-N-(4-(1-cyclohexen-1-yl)benzoyl)-3-nitrobenzenesulfonamideEXAMPLE 68A N-(1-adamantylmethyl)-2-(phenylsulfanyl)acetamide

A room temperature solution of (phenylsulfanyl)acetic acid (1.68 g, 10.0mmol) in dichloromethane (10 mL) was treated with 2M oxalyl chloride indichloromethane (8 mL, 16.0 mmol) and DMF (1 drop), stirred for 2 hours,concentrated, dissolved in dichloromethane (10 mL), treated with1-adamantylmethylamine (1.65 g, 10.0 mmol) and N,N-diisopropylethylamine(2.1 mL, 12.0 mmol), and stirred for 1 hour. The mixture was filteredthrough a pad of silica gel (20 g) and concentrated to provide thedesired product of sufficient purity for subsequent use.

EXAMPLE 68B N-(1-adamantylmethyl)-2-(phenylsulfanyl)ethanamine

A solution of Example 68A in THF (5 mL)was treated with 1M LAH in THF(20 mL, 20.0 mmol), heated to reflux, stirred for 24 hours, cooled toroom temperature, treated sequentially with water (0.8 mL), 15% NaOH(0.8 mL), and water (2.4 mL), stirred for 30 minutes, filtered throughdiatomaceous earth (Celite®), and concentrated. The concentrate waspurified by flash column chromatography on silica gel with 20-100% ethylacetate/hexanes to provide the desired product.

EXAMPLE 68C4-((1-adamantylmethyl)(2-(phenylsulfanyl)ethyl)amino)-N-(4-(1-cyclohexen-1-yl)benzoyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 9B and Example68B for Example 7C and Example 1D, respectively, in Example 7D. MS(ESI(−)) m/e 684 (M−H)⁻; ¹H NMR (400 MHz, DMSO-d₆) δ8.69 and 8.60 (2brs, 1H total), 8.92 and 8.38 (2d, 1H), 8.16 and 8.06 (2dd, 1H), 7.60 (t,2H), 7.46 (dd, 2H), 7.40 (d, 1H), 7.35-7.10 (m, 5H), 6.28 (m, 1H),3.40-2.90 (m, 6H), 2.40 (m, 2H), 2.23 (m, 2H), 2.05-1.20 (m, 19H).

EXAMPLE 694-(benzhydrylamino)-N-((4′-fluoro(1,1′-biphenyl)-4-yl)carbonyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting benzhydrylamine for2,2-dimethylcyclopentylamine in Example 1E. MS (APCI(+)) m/e 582 (M+H)⁺;¹H NMR (500 MHz, DMSO-d₆) δ12.55 (br s, 1H), 8.88 (d, 1H), 8.71 (d, 1H),7.96 (dd, 1H), 7.94 (d, 2H), 7.80-7.76 (m, 4H), 7.48-7.46 (m, 4H),7.41-7.37 (m, 4H), 7.34-7.29 (m, 4H), 7.05 (d, 1H), 6.19 (d, 1H).

EXAMPLE 704-((1,2-diphenylethyl)amino)-N-((4′-fluoro(1,1′-biphenyl)-4-yl)carbonyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting 1,2-diphenylethanaminefor 2,2-dimethylcyclopentylamine in Example 1E. MS (APCI(+)) m/e 613(M+NH₄)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ12.45 (br s, 1H), 8.81 (d, 1H),8.63 (d, 1H), 7.93 (d, 2H), 7.86 (dd, 1H), 7.81-7.76 (m, 4H), 7.48 (d,2H), 7.37-7.26 (m, 9H), 7.22-7.18 (m, 1H), 7.03 (d, 1H), 5.19 (ddd, 1H),3.30 (dd, 1H), 1.61 (dd, 1H).

EXAMPLE 714-((1-cyclohexyl-2-(phenylsulfanyl)ethyl)amino)-N-((4′-fluoro(1,1′-biphenyl)-4-yl)carbonyl)-3-nitrobenzenesulfonamideEXAMPLE 71A 1-cyclohexyl-2-(phenylsulfanyl)ethanol

A room temperature solution of vinylcyclohexane (1.71 g, 15.5 mmol) indichloromethane (20 mL) was treated with 70% mCPBA (4.90 g, 19.9 mmol),stirred for 3 hours, diluted with diethyl ether (100 mL), washed withsaturated NaHCO₃ and brine, dried (MgSO₄), filtered, and concentrated.The concentrate was dissolved in 1,2-dichloroethane (20 mL), treatedwith thiophenol (1.8 g, 16.3 mmol), heated to 80° C., stirred for 5hours, and concentrated. The concentrate was purified by flash columnchromatography on silica gel with 20% ethyl acetate/hexanes to providethe desired product. MS (DCI/NH₃) m/e 254 (M+NH₄).

EXAMPLE 71B 1-cyclohexyl-2-(phenylsulfanyl)ethanamine

The desired product was prepared by substituting Example 71A for Example7A in Examples 7B and 7C.

EXAMPLE 71C4-((1-cyclohexyl-2-(phenylsulfanyl)ethyl)amino)-N-((4′-fluoro(1,1′-biphenyl)-4-yl)carbonyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 71B for Example7C in Example 7D. MS (ESI(−)) m/e 632 (M−H)⁻; ¹H NMR (400 MHz, DMSO-d₆)δ8.55 (d, 1H), 8.20 (t, 1H), 8.02-7.72 (m, 4H), 7.43-7.10 (m, 11H),3.20-3.15 (m, 3H), 1.60-1.00 (m, 11H).

EXAMPLE 72N-(4-(1-cyclohexen-1-yl)benzoyl)-4-((1-cyclohexyl-2-(phenylsulfanyl)ethyl)amino)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 71B and Example9B for Example 7C and Example 1D in Example 7. MS (ESI(−)) m/e 618(M−H)⁻; ¹H NMR (400 MHz, DMSO-d₆) δ8.70 (m, 1H), 8.53 (d, 1H), 7.73 (m,3H), 7.49 (m, 2H), 7.28 (m, 2H), 7.20-7.06 (m, 4H), 6.32 (m, 1H),4.05-3.48 (m, 3H), 2.37 (m, 2H), 2.19 (m, 2H), 2.00-1.10 (m, 15H).

EXAMPLE 734-((2E)-2-(3,4-dihydro-1(2H)-naphthalenylidene)hydrazino)-N-((4′-fluoro(1,1′-biphenyl)-4-yl)carbonyl)-3-nitrobenzenesulfonamideEXAMPLE 73A tert-butyl2-(4-(aminosulfonyl)-2-nitrophenyl)hydrazinecarboxylate

A solution of Example 1D (212 mg, 0.49 mmol) and tert-butylcarbazate(976 mg, 2.3 mmol) in ethanol (5 mL) was heated to reflux, stirred for16 hours, diluted with ethyl acetate (50 mL), washed with water andbrine, dried (MgSO₄), filtered, and concentrated. The concentrate waspurified by flash column chromatography on silica gel with1:0.5:98.5/methanol:acetic acid:dichloromethane, then2:0.5:97.5/methanol:acetic acid:dichloromethane to provide the desiredproduct. MS (ESI(−)) m/e 331 (M−H)⁻.

EXAMPLE 73B4-((2E)-2-(3,4-dihydro-1(2H)-naphthalenylidene)hydrazino)-3-nitrobenzenesulfonamide

A room temperature solution of Example 73A (145 mg, 0.44 mmol) in 1:1TFA/dichloromethane (10 mL) was stirred for 4 hours and concentrated.The concentrate was dissolved in ethanol (2 mL), treated with3,4-dihydro-1(2H)-naphthalenone (8.2 mg, 0.06 mmol) and pyridiniump-toluenesulfonate (2 mg, 0.008 mmol), heated to reflux, stirred for 2hours, cooled to room temperature, and concentrated. The concentrate waspurified by flash column chromatography on silica gel with 4%methanol/dichloromethane to provide the desired product. MS (ESI(−)) m/e359 (M−H)⁻.

EXAMPLE 73C4-((2E)-2-(3,4-dihydro-1(2H)-naphthalenylidene)hydrazino)-N-((4′-fluoro(1,1′-biphenyl)-4-yl)carbonyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 73B for Example1C in Example 1D. MS (ESI(−)) m/e 557 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆)δ11.10 (s, 1H), 8.70 (t, 1H), 8.19 (dd, 1H), 8.14 (s, 2H), 7.96 (dt,2H), 7.80-7.70 (m, 4H), 7.36-7.23 (m, 5H), 2.80 (m, 4H), 1.95 (m, 2H).

EXAMPLE 744-((3-cyclohexylpropyl)amino)-N-((4′-fluoro(1,1′-biphenyl)-4-yl)carbonyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting3-cyclohexyl-1-propanamine and Example 1D for cyclohexylamine andExample 1C, respectively, in Example 3A. MS (ESI(+)) m/e 540 (M+H)⁺; ¹HNMR (300 MHz, DMSO-d₆) δ8.59 (d, 1H), 8.47 (t, 1H), 7.95 (m, 3H), 7.75(dd, 2H), 7.68 (d, 2H), 7.30 (dd, 2H), 7.13 (d, 1H), 3.39 (m, 2H),1.71-1.55 (m, 6H), 1.29-1.12 (m, 7H), 0.93-0.79 (m, 2H).

EXAMPLE 75N-((4′-fluoro(1,1′-biphenyl)-4-yl)carbonyl)-3-nitro-4-(2-(phenylsulfanyl)ethoxy)benzenesulfonamideEXAMPLE 75AN-((4′-fluoro(1,1′-biphenyl)-4-yl)carbonyl)-4-(2-hydroxyethoxy)-3-nitrobenzenesulfonamide

A room temperature solution of NaH (1.52 g, 38.0 mmol) in DMF (100 mL)was treated with ethylene glycol (4.23 mL, 76.0 mmol) over 10 minutes,then treated sequentially with 15-crown-5 (7.54 mL, 38.0 mmol) andExample 1D (3.30 g, 7.6 mmol), and stirred for 30 minutes, quenched with1M HCl, and extracted with ethyl acetate. The combined extracts werewashed with water and brine, dried (Na₂SO₄), filtered, and concentrated.The concentrate was purified by flash column chromatography on silicagel with ethyl acetate to provide the desired product. MS (ESI(+)) m/e461 (M+H)⁺.

EXAMPLE 75BN-((4′-fluoro(1,1′-biphenyl)-4-yl)carbonyl)-3-nitro-4-(2-(phenylsulfanyl)ethoxy)benzenesulfonamide

The desired product was prepared by substituting Example 75A for Example27A in Example 27B. MS (ESI(−)) m/e 551 (M−H)⁻; ¹H NMR (300 MHz,DMSO-d₆) δ8.29 (d, 1H), 8.04 (dd, 1H), 7.96 (d, 2H), 7.73 (dd, 2H), 7.61(d, 2H), 7.40 (d, 2H), 7.39 (s, 1H), 7.32 (d, 2H), 7.28 (d, 2H), 7.21(dd, 1H), 4.39 (t, 2H), 3.40 (t, 2H).

EXAMPLE 76N-(4-(1-cyclohexen-1-yl)benzoyl)-3-nitro-4-((2-(phenylsulfonyl)ethyl)amino)benzenesulfonamideEXAMPLE 76A 2-(phenylsulfonyl)ethanamine

A mixture of ((2-chloroethyl)sulfonyl)benzene (1.02 g, 5.0 mmol),potassium phthalimide (1.02 g, 5.5 mmol), 18-crown-6 (50 mg), andtetrabutylammonium iodide (50 mg) in dioxane was heated to reflux,stirred for 24 hours, cooled to room temperature, diluted with ethylacetate (100 mL), washed with water and brine, dried (MgSO₄), filtered,and concentrated. The concentrate was dissolved in ethanol (10 mL),treated with hydrazine hydrate (1 mL), heated to reflux, stirred for 2hours, cooled to room temperature, filtered through diatomaceous earth(Celite®), and rinsed with ethyl acetate. The filtrate was treated withethyl acetate, washed with water and brine, dried (MgSO₄), filtered, andconcentrated. The concentrate was dissolved in diethyl ether (5 mL),treated with 1M HCl in diethyl ether (10 mL), and filtered. The solidwas washed with diethyl ether, suspended in ethyl acetate (80 mL),washed with 2M Na₂CO₃ and brine, dried (MgSO₄), filtered, andconcentrated to provide the desired product.

EXAMPLE 76BN-(4-(1-cyclohexen-1-yl)benzoyl)-3-nitro-4-((2-(phenylsulfonyl)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 76A and Example9B for Example 7C and Example 1D, respectively, in Example 7D. MS(ESI(−)) m/e 568 (M−H)⁻; ¹H NMR (400 MHz, DMSO-d₆) δ8.59 (d, 1H), 8.57(t, 1H), 7.93 (dd, 1H), 7.84 (m, 4H), 7.67 (m, 1H), 7.56 (d, 2H), 7.51(d, 2H), 7.14 (d, 1H), 6.33 (m, 1H), 3.79 (s, 2H), 2.38 (m, 2H), 2.19(m, 2H), 1.72 (m, 2H), 1.59 (m, 2H).

EXAMPLE 77N-(4-(4,4-dimethylcyclohexyl)benzoyl)-3-nitro-4-((2-(phenylsulfanyl)ethyl)amino)benzenesulfonamideEXAMPLE 77A methyl 4-(4,4-dimethylcyclohexyl)benzoate

The desired product was prepared by substituting4,4-dimethylcyclohexanone for 4-tert-butylcyclohexanone in Examples5A-5C. MS (DCI) m/e 247 (M+H)⁺.

EXAMPLE 77B 3-nitro-4-((2-(phenylsulfanyl)ethyl)amino)benzenesulfonamide

A solution Example 1C (2.36 g, 10.0 mmol), 2-(phenylsulfanyl)ethanamine(1.68 g, 11.0 mmol), and triethylamine in dioxane (5 mL) was heated to80° C., stirred for 16 hours, diluted with ethyl acetate (100 mL),washed sequentially with 3M HCl, water, and brine, dried (MgSO₄),filtered, and concentrated to provide the desired product. MS (DCI) m/e354 (M+H)⁺.

EXAMPLE 77CN-(4-(4,4-dimethylcyclohexyl)benzoyl)-3-nitro-4-((2-(phenylsulfanyl)ethyl)amino)benzenesulfonamide

The procedure used in Example 5 was used here to convert the productsfrom Examples 78A and 78B to the title compound. MS (ESI(−)) m/e 566(M−H)⁻; ¹H NMR (400 MHz, DMSO-d₆) δ8.80 (t, 1H), 8.61 (d, 1H), 7.91 (dd,1H), 7.79 (d, 2H), 7.48 (m, 4H), 7.40-7.15 (m, 4H), 3.66 (q, 2H), 3.29(t, 2H), 2.49 (m, 1H) 1.65-1.20 (m, 8H), 0.96 (s, 3H), 0.93 (s, 3H).

EXAMPLE 78N-((4′-fluoro(1,1′-biphenyl)-4-yl)carbonyl)-4-((2-((2-methylphenyl)sulfanyl)ethyl)amino)-3-nitrobenzenesulfonamideEXAMPLE 78AN-((4′-fluoro(1,1′-biphenyl)-4-yl)carbonyl)-4-((2-hydroxyethyl)amino)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting 2-aminoethanol andExample 1D for cyclohexylamine and Example 1C, respectively, in Example3A. MS (ESI(−)) m/e 458 (M−H)⁻.

EXAMPLE 78BN-((4′-fluoro(1,1′-biphenyl)-4-yl)carbonyl)-4-((2-((2-methylphenyl)sulfanyl)ethyl)amino)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting 2-methylbenzenethioland Example 78A for Example 27A and thiophenol, respectively, in Example27B. MS (ESI(−)) m/e 564 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ8.54 (t,1H), 8.52 (d, 1H), 7.95 (d, 2H), 7.87 (dd, 1H), 7.74 (dd, 2H), 7.59 (d,2H), 7.45-7.37 (m, 1H), 7.28 (t, 2H), 7.23-7.08 (m, 3H), 6.98 (d, 1H),3.59 (dt, 2H), 3.25 (t, 2H), 2.28 (s, 3H).

EXAMPLE 794-((2-((2-chlorophenyl)sulfanyl)ethyl)amino)-N-((4′-fluoro(1,1′-biphenyl)-4-yl)carbonyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting 2-chlorobenzenethioland Example 78A for thiophenol and Example 27A, respectively, in Example27B. MS (ESI(−)) m/e 584 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ8.60 (t,1H), 8.55 (d, 1H), 7.98-7.88 (m, 3H), 7.75 (dd, 2H), 7.63 (d, 2H), 7.54(dd, 1H), 7.45 (dd, 1H), 7.34-7.25 (m, 3H), 7.19 (td, 1H), 7.12 (d, 1H),3.67 (dt, 2H), 3.28 (t, 2H).

EXAMPLE 80N-((4′-fluoro(1,1′-biphenyl)-4-yl)carbonyl-3-nitro-4-((2-((2-(trifluoromethyl)phenyl)sulfanyl)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting2-(trifluoromethyl)benzenethiol and Example 78A for thiophenol andExample 27A, respectively, in Example 27B. MS (ESI(−)) m/e 618 (M−H)⁻;¹H NMR (300 MHz, DMSO-d₆) δ8.52 (d, 1H), 8.50 (t, 1H), 7.95 (d, 2H),7.90 (dd, 1H), 7.78-7.67 (m, 4H), 7.61 (d, 3H), 7.38 (t, 1H), 7.28 (t,2H), 7.05 (d, 1H), 3.64 (dt, 2H), 3.38 (t, 2H).

EXAMPLE 81N-((4′-fluoro(1,1′-biphenyl)-4-yl)carbonyl)-4-((2-((3-methylphenyl)sulfanyl)ethyl)amino)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting 3-methylbenzenethioland Example 78A for thiophenol and Example 27A, respectively, in Example27B. MS (ESI(−)) m/e 564 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ8.56 (t,1H), 8.54 (d, 1H), 7.95 (d, 2H), 7.89 (dd, 1H), 7.75 (dd, 2H), 7.64 (d,2H), 7.28 (t, 2H), 7.22-7.15 (m, 3H), 7.06-6.96 (m, 2H), 3.62 (dt, 2H),3.25 (t, 2H), 2.25 (s, 3H).

EXAMPLE 82N-((4′-fluoro(1,1′-biphenyl)-4-yl)carbonyl)-4-((2-((4-methylphenyl)sulfanyl)ethyl)amino)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting 4-methylbenzenethioland Example 78A for thiophenol and Example 27A in Example 27B. MS(ESI(−)) m/e 564 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ8.78 (t, 1H), 8.61(d, 1H), 7.96 (d, 2H), 7.92 (dd, 1H), 7.80 (m, 4H), 7.37-7.24 (m, 4H),7.20 (d, 1H), 7.07 (d, 2H), 3.64 (dt, 2H), 3.23 (t, 2H), 2.24 (s, 3H).

EXAMPLE 83N-((4′-fluoro(1,1′-biphenyl)-4-yl)carbonyl)-3-nitro-4-((2-((4-nitrophenyl)sulfanyl)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting 4-nitrobenzenethiol andExample 78A for thiophenol and Example 27A, respectively, in Example27B. MS (ESI(−)) m/e 595 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ8.56 (t,1H), 8.51 (d, 1H), 8.11 (d, 2H), 7.97-7.89 (m, 3H), 7.74 (dd, 2H),7.64-7.56 (m, 4H), 7.28 (t, 2H), 7.14 (d, 1H), 3.72 (dt, 2H), 3.45 (t,2H).

EXAMPLE 844-((2-((2,4-difluorophenyl)sulfanyl)ethyl)amino)-N-((4′-fluoro(1,1′-biphenyl)-4-yl)carbonyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting2,4-difluorobenzenethiol and Example 78A for thiophenol and Example 27A,respectively, in Example 27B. MS (ESI(−)) m/e 586 (M−H)⁻; ¹H NMR (300MHz, DMSO-d₆) δ8.51 (d, 1H), 8.47 (t, 1H), 7.95 (d, 2H), 7.89 (dd, 1H),7.74 (dd, 2H), 7.62-7.53 (m, 3H), 7.34-7.23 (m, 3H), 7.11-7.03 (m, 1H),7.00 (d, 1H), 3.57 (dt, 2H), 3.21 (t, 2H).

EXAMPLE 854-((2-((2,4-dimethylphenyl)sulfanyl)ethyl)amino)-N-((4′-fluoro(1,1′-biphenyl)-4-yl)carbonyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting2,4-dimethylbenzenethiol and Example 78A for thiophenol and Example 27A,respectively, in Example 27B. MS (ESI(−)) m/e 578 (M−H)⁻; ¹H NMR (300MHz, DMSO-d₆) δ8.52 (t, 1H), 8.50 (d, 1H), 7.95 (d, 2H), 7.87 (dd, 1H),7.73 (dd, 2H), 7.60 (d, 2H), 7.34-7.24 (m, 3H), 7.03-6.92 (m, 3H), 3.54(dt, 2H), 3.18 (t, 2H), 2.27 (s, 3H), 2.22 (s, 3H).

EXAMPLE 86N-(4-(2-methyl-1,3-benzoxazol-5-yl)benzoyl)-3-nitro-4-((2-(phenylsulfanyl)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 54B and Example77B for Example 1B and Example 1C, respectively, in Example 1D. MS(ESI(−)) m/e 587 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ8.53 (t, 1H), 8.52(d, 1H), 7.99-7.86 (m, 4H), 7.69 (dd, 2H), 7.65 (d, 2H), 7.40 (d, 2),7.31 (t, 2H), 7.20 (t, 1H), 7.00 (d, 1H), 3.51 (dt, 2H), 3.28 (t, 2H),2.63 (s, 3H).

EXAMPLE 874-((3,3-diphenylpropyl)amino)-N-((4′-fluoro(1,1′-biphenyl)-4-yl)carbonyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting3,3-diphenyl-1-propanamine for 2,2-dimethylcyclopentylamine in Example1E. MS (APCI(+)) m/e 627 (M+NH₄)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ12.45 (brs, 1H), 8.65 (d, 1H), 8.61 (t, 1H), 7.97 (d, 2H), 7.93 (dd, 1H),7.82-7.78 (m, 4H), 7.36-7.33 (m, 6H), 7.30-7.27 (m, 4H), 7.19-7.16 (m,2H), 7.08 (d, 1H), 4.12 (t, 1H), 3.40 (d, 1H), 3.37 (d, 1H), 2.45 (d,1H), 2.42 (d, 1H).

EXAMPLE 884-((2-(benzylsulfanyl)ethyl)amino)-N-((4′-fluoro(1,1′-biphenyl)-4-yl)carbonyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting2-(benzylsulfanyl)ethanamine and Example 1D for cyclohexylamine andExample 1C, respectively, in Example 3A. MS (ESI(−)) m/e 564 (M−H)⁻; ¹HNMR (300 MHz, DMSO-d₆) δ8.54 (d, 1H), 8.52 (t, 1H), 7.96 (d, 2H), 7.90(dd, 1H), 7.73 (m, 2H), 7.62 (t, 2H), 7.37-7.20 (m, 7H), 7.00 (d, 1H),3.81 (s, 2H), 3.56 (dt, 2H), 2.70 (t, 2H).

EXAMPLE 89N-((4′-fluoro(1,1′-biphenyl)-4-yl)carbonyl)-3-nitro-4-(3-(phenylsulfanyl)propoxy)benzenesulfonamideEXAMPLE 89AN-((4′-fluoro(1,1′-biphenyl)-4-yl)carbonyl)-4-(3-hydroxypropoxy)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting 1,3-propanediol forethylene glycol in Example 75A. MS (ESI(−)) m/e 473 (M−H)⁻.

EXAMPLE 89BN-((4′-fluoro(1,1′-biphenyl)-4-yl)carbonyl)-3-nitro-4-(3-(phenylsulfanyl)propoxy)benzenesulfonamide

The desired product was prepared by substituting Example 89A for Example27A in Example 27B. MS (ESI(−)) m/e 565 (M−H)⁻; ¹H NMR (300 MHz,DMSO-d₆) δ8.29 (d, 1H), 8.06 (dd, 1H), 7.96 (d, 2H), 7.74 (dd, 2H), 7.62(d, 2H), 7.39-7.24 (m, 7H), 7.14 (tt, 1H), 4.29 (t, 2H), 3.13 (t, 2H),2.02 (m, 2H).

EXAMPLE 90N-((4′-fluoro(1,1′-biphenyl)-4-yl)carbonyl)-4-(3-((2-methylphenyl)sulfanyl)propoxy)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting 2-methylbenzenethioland Example 89A for thiophenol and Example 27A, respectively, in Example27B. MS (ESI(−)) m/e 579 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ8.31 (d,1H), 8.06 (dd, 1H), 7.96 (d, 2H), 7.74 (dd, 2H), 7.63 (d, 2H), 7.38 (d,1H), 7.28 (t, 3H), 7.16 (dd, 2H), 7.05 (td, 1H), 4.31 (t, 2H), 3.10 (t,2H), 2.26 (s, 3H), 2.04 (m, 2H).

EXAMPLE 91N-((4′-fluoro(1,1′-biphenyl)-4-yl)carbonyl)-3-nitro-4-(3-((2-(trifluoromethyl)phenyl)sulfanyl)propoxy)benzenesulfonamide

The desired product was prepared by substituting2-trifluoromethylbenzenethiol and Example 89A for thiophenol and Example27A, respectively, in Example 27B. MS (ESI(−)) m/e 633 (M−H)⁻; ¹H NMR(300 MHz, DMSO-d₆) δ8.31 (d, 1H), 8.06 (dd, 1H), 7.96 (d, 2H), 7.77-7.70(m, 3H), 7.69-7.54 (m, 4H), 7.38 (m, 2H), 7.28 (t, 2H), 4.30 (t, 2H),3.24 (t, 2H), 2.05 (m, 2H).

EXAMPLE 924-(3-((2,4-difluorophenyl)sulfanyl)propoxy)-N-((4′-fluoro(1,1′-biphenyl)-4-yl)carbonyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting2,4-difluorobenzenethiol and Example 89A for thiophenol and Example 27A,respectively, in Example 27B. MS (ESI(−)) m/e 601 (M−H)⁻; ¹H NMR (300MHz, DMSO-d₆) δ8.28 (d, 1H), 8.07 (dd, 1H), 7.96 (d, 2H), 7.74 (dd, 2H),7.62 (d, 2H), 7.59-7.48 (m, 1H), 7.38 (d, 1H), 7.35-7.25 (m, 3H),7.12-7.04 (m, 1H), 4.29 (t, 2H), 3.08 (t, 2H), 1.97 (m, 2H).

EXAMPLE 93N-((4′-fluoro(1,1′-biphenyl)-4-yl)carbonyl)-4-(neopentylamino)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting2,2-dimethyl-1-propanamine for 2,2-dimethylcyclopentylamine in Example1E. MS (APCI(+)) m/e 486 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ12.45 (br s,1H), 8.70 (d, 1H), 8.58 (t, 1H), 7.99 (dd, 1H), 7.97 (d, 2H), 7.81 (2d,4H), 7.38 (d, 1H), 7.34 (t, 2H), 3.30 (d, 2H), 1.02 (s, 9H).

EXAMPLE 944-(2-adamantylamino)-N-((4′-fluoro(1,1′-biphenyl)-4-yl)carbonyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting 2-adamantanaminehydrochloride for 2-aminoborane hydrochloride in Example 13. MS(APCI(+)) m/e 550 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ12.45 (br s, 1H),8.83 (d, 1H), 8.70 (d, 1H), 7.98 (dd, 1H), 7.95 (d, 2H), 7.78 (2d, 4H),7.32 (t, 2H), 7.30 (d, 1H), 4.01 (m, 1H), 2.04-1.65 (m, 14H).

EXAMPLE 954-((1-adamantylmethyl)amino)-N-(4-(1-isopropyl-2-methyl-1H-benzimidazol-5-yl)benzoyl)-3-nitrobenzenesulfonamideEXAMPLE 95A methyl 4′-fluoro-3′-nitro(1,1′-biphenyl)-4-carboxylate

The desired product was prepared by substituting4-bromo-1-fluoro-2-nitrobenzene for Example 5A in Example 5B.

EXAMPLE 95B methyl 4-(1-ethyl-2-methyl-1H-benzimidazol-5-yl)benzoate

A room temperature solution of Example 95A (275 mg, 1.0 mmol) inisopropylamine (2 mL) was stirred for 16 hours and concentrated. Theconcentrate was suspended in dichloromethane (5 mL) and filtered througha pad of silica gel (5 g) with 1:1 dichloromethane/diethyl ether, andconcentrated.

The concentrate was dissolved in ethyl acetate (5 mL), treated with 10%Pd/C (100 mg), then stirred under a hydrogen atmosphere for 3 hours. Themixture was filtered through a pad of silica gel (10 g) with ethylacetate and concentrated.

The concentrate was dissolved in acetic acid (5 mL), treated with aceticanhydride (0.5 mL), heated to reflux, stirred for 16 hours, andconcentrated. The concentrate was dissolved in ethyl acetate (50 mL),washed sequentially with saturated NaHCO₃, water, and brine, dried(MgSO₄), filtered, and concentrated. The concentrate was purified byflash column chromatography on silica gel with 2-8%methanol/dichloromethane to provide the desired product. MS (DCI) m/e309 (M+H)⁺.

EXAMPLE 95C4-((1-adamantylmethyl)amino)-N-(4-(1-isopropyl-2-methyl-1H-benzimidazol-5-yl)benzoyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 95B and Example28A for Example 5C and Example 3A, respectively, in Example 5D. MS(ESI(−)) m/e 640 (M−H)⁻; ¹H NMR (400 MHz, DMSO-d₆) δ8.52 (d, 1H), 8.39(t, 1H), 7.95 (d, 2H), 7.89 (dd, 1H), 7.78 (s, 1H), 7.70 (d, 1H), 7.62(d, 2H), 7.48 (d, 1H), 7.16 (d, 1H), 4.75 (m, 1H), 3.12 (d, 2H), 2.57(s, 3H), 1.97 (m, 3H), 1.73-1.50 (m, 18H).

EXAMPLE 96N-((4′-fluoro(1,1′-biphenyl)-4-yl)carbonyl)-3-nitro-4-((2-(phenylsulfanyl)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting2-(phenylsulfanyl)ethanamine for 2,2-dimethylcyclopentylamine in Example1E. MS (APCI(+)) m/e 569 (M+NH₄)⁺, ¹H NMR (500 MHz, DMSO-d₆) δ12.40 (brs, 1H), 8.68 (t, 1H), 8.53 (d, 1H), 7.86 (d, 2H), 7.84 (dd, 1H), 7.69(2d, 4H), 7.27 (dd, 2H), 7.22 (t, 2H), 7.17 (t, 2H), 7.12 (d, 1H), 7.08(t, 1H), 3.60-3.56 (m, 2H), 3.21-3.18 (m, 2H).

EXAMPLE 97N-(4-(1-cyclohexen-1-yl)benzoyl)-3-nitro-4-((2-(phenylsulfanyl)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 9A and Example77B for Example 5C and Example 3A, respectively, in Example 5D. MS(ESI(−)) m/e 536 (M−H)⁻; ¹H NMR (400 MHz, CD₃OD) δ8.77 (d, 1H), 7.99(dd, 1H), 7.77 (d, 2H), 7.47 (d, 2H), 7.38 (m, 2H), 7.20 (m, 2H), 7.14(m, 1H), 7.02 (d, 1H), 6.27 (m, 1H), 3.67 (t, 2H), 3.27 (t, 2H), 2.41(m, 2H), 2.22 (m, 2H), 1.79 (m, 2H), 1.67 (m, 2H).

EXAMPLE 984-(cyclohexyloxy)-N-((4′-fluoro(1,1′-biphenyl)-4-yl)carbonyl)-3-(trifluoromethyl)benzenesulfonamideEXAMPLE 98A 4-chloro-3-(trifluoromethyl)benzenesulfonamide

A −10° C. solution of 4-chloro-3-(trifluoromethyl)aniline (5.37 g, 27.5mmol) in acetic acid (25 mL) and concentrated HCl (30 mL) was treatedwith a solution of NaNO₂ (2.09 g, 30.3 mmol) in water (10 mL), stirredfor 20 minutes, and poured into a saturated solution of SO₂ andCuCl₂.2H₂O (1.70 g, 10 mmol) in acetic acid (80 mL) and water (10 mL).The reaction was stirred for 1 hour, poured into ice, and extracted withdichloromethane. The combined extracts were washed with brine andconcentrated. The concentrate was dissolved in saturated NH₄OH (150 mL)and THF (150 mL), stirred for 30 minutes, and extracted with ethylacetate. The combined extracts were washed with brine, dried (Na₂SO₄),filtered, and concentrated. The concentrate was purified by flash columnchromatography on silica gel with 10% ethyl acetate/hexanes to providethe desired product. MS (DCI) m/e 277 (M+NH₄)⁺.

EXAMPLE 98B 4-(cyclohexyloxy)-3-(trifluoromethyl)benzenesulfonamide

A 0° C. solution of KH (8.7 g, 76.0 mmol) in DMF (100 mL) was treatedwith cyclohexanol (8.02 mL, 76.0 mmol) over 10 minutes, then treatedwith 18-crown-6 (7.9 g, 30.0 mmol) and Example 98A (3.95 g, 15.2 mmol),heated to 100° C., and stirred for 30 minutes. The reaction was cooledto room temperature, quenched with 1M HCl, and extracted with ethylacetate. The combined extracts were washed with water and brine, dried(Na₂SO₄), filtered, and concentrated. The concentrate was purified byflash column chromatography on silica gel with 50% ethyl acetate/hexanesto provide the desired product. MS (ESI) m/e 322 (M−H)⁻.

EXAMPLE 98C4-(cyclohexyloxy)-N-((4′-fluoro(1,1′-biphenyl)-4-yl)carbonyl)-3-(trifluoromethyl)benzenesulfonamide

The desired product was prepared by substituting Example 98B for Example1C in Example 1D. MS (ESI(−)) m/e 520 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆)δ8.28 (d, 1H), 8.20 (dd, 1H), 8.15 (d, 2H), 7.99 (d, 2H), 7.90 (d, 2H),7.78 (dd, 1H), 7.56 (d, 1H), 4.79 (m, 1H), 2.82 (s, 3H), 1.88 (m, 2H),1.65 (m, 4H), 1.43 (m, 4H).

EXAMPLE 994-(cyclohexyloxy)-N-(4-(2-methyl-1,3-benzothiazol-5-yl)benzoyl)-3-(trifluoromethyl)benzenesulfonamide

The desired product was prepared by substituting Example 98B and Example17A for Example 1C and Example 1B, respectively, in Example 1D. MS (ESI)m/e 573 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ8.19 (d, 1H), 8.08 (m, 2H),7.99 (d, 2H), 7.73 (m, 4H), 7.31 (d, 1H), 4.65 (m, 1H), 2.82 (s, 3H),1.87 (m, 2H), 1.75-1.35 (m, 8H).

EXAMPLE 1004-((cyclohexylmethyl)amino)-N-((4′-fluoro(1,1′-biphenyl)-4-yl)carbonyl)-3-nitro-5-vinylbenzenesulfonamideEXAMPLE 100A4-((cyclohexylmethyl)amino)-3-nitro-5-vinylbenzenesulfonamide

The desired product was prepared by substituting tributyl(vinyl)stannanefor 2-(tributylstannyl)pyrimidine in Example 26B. MS (ESI) m/e 338(M−H)⁻.

EXAMPLE 100B4-((cyclohexylmethyl)amino)-N-((4′-fluoro(1,1′-biphenyl)-4-yl)carbonyl)-3-nitro-5-vinylbenzenesulfonamide

The desired product was prepared by substituting Example 100A forExample 1C in Example 1D. MS (ESI) m/e 536 (M−H)⁻; ¹H NMR (300 MHz,DMSO-d₆) δ8.39 (d, 1H), 7.98-7.93 (m, 3H), 7.74 (dd, 2H), 7.61 (d, 2H),7.47 (t, 1H), 7.28 (t, 2H), 6.92 (dd, 1H), 5.65 (d, 1H), 5.40 (d, 1H),3.18 (t, 2H), 1.70-1.53 (m, 5H), 1.25-1.04 (m, 3H), 0.94-0.80 (m, 3H).

EXAMPLE 1014-((2-((2,6-dimethylphenyl)sulfanyl)ethyl)amino)-N-((4′-fluoro(1,1′-biphenyl)-4-yl)carbonyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting2,6-dimethylbenzenethiol and Example 78A for thiophenol and Example 27A,respectively, in Example 27B. MS (ESI) m/e 578 (M−H)⁻; ¹H NMR (300 MHz,DMSO-d₆) δ8.53 (d, 1H), 8.48 (t, 1H), 7.95 (d, 2H), 7.85 (dd, 1H), 7.73(dd, 2H), 7.62 (d, 2H), 7.28 (t, 2H), 7.19-7.09 (m, 3H), 6.83 (d, 1H),3.45 (dt, 2H), 2.97 (t, 2H), 2.46 (s, 6H).

EXAMPLE 1024-((2-((2-bromophenyl)sulfanyl)ethyl)amino)-N-((4′-fluoro(1,1′-biphenyl)-4-yl)carbonyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting 2-bromobenzenethiol andExample 78A for thiophenol and Example 27A, respectively, in Example27B. MS (ESI(−)) m/e 628 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ8.61 (t,1H), 8.56 (d, 1H), 7.98-7.89 (m, 3H), 7.75 (dd, 2H), 7.64 (d, 2H), 7.59(dd, 1H), 7.52 (dd, 1H), 7.36 (td, 1H), 7.28 (t, 2H), 7.15-7.06 (m, 2H),3.68 (dt, 2H), 3.27 (t, 2H).

EXAMPLE 103N-((4′-fluoro(1,1′-biphenyl)-4-yl)carbonyl)-4-((2-methyl-2-(phenylsulfanyl)propyl)amino)-3-nitrobenzenesulfonamideEXAMPLE 103A methyl (phenylsulfanyl)acetate

A room temperature solution of (phenylsulfanyl)acetic acid (8.4 g, 50.0mmol) in methanol (100 mL) was treated with chlorotrimethylsilane (13mL, 100.0 mmol), stirred for 16 hours, and concentrated. The concentratewas dissolved in 5:1/hexanes:diethyl ether, filtered through a pad ofsilica gel (80 g), rinsed with 5:1/hexanes:diethyl ether, andconcentrated to provide the desired product.

EXAMPLE 103B methyl 2-methyl-2-(phenylsulfanyl)propanoate

A −78° C. solution of Example 103A (911 mg, 5.0 mmol) and iodomethane(2.2 g, 15.0 mmol) in THF (20 mL) was treated with 1.0M sodiumhexamethyldisilazide in THF (11 mL, 11.0 mmol), warmed to roomtemperature over 16 hours, diluted with hexanes (50 mL), filteredthrough a pad of silica gel, and concentrated. The concentrate waspurified by flash column chromatography on silica gel with 5% ethylacetate/hexanes to provide the desired product. MS (DCI) m/e 211 (M+H)⁺.

EXAMPLE 103C 2-methyl-2-(phenylsulfanyl)-1-propanol

A −78° C. solution of Example 103B (860 mg, 4.1 mmol) in dichloromethane(10 mL) was treated with 1.0M DIBAL-H in toluene (11 mL), warmed to roomtemperature over 4 hours, poured into a mixture of 3M HCl (15 mL) andice (˜10 g), and extracted with ethyl acetate (100 mL). The combinedextracts were washed with 1M HCl (10 mL) and brine (10 mL), dried(MgSO₄), filtered, and concentrated. The concentrate was purified byflash column chromatography on silica gel with 10-30% ethylacetate/hexanes to provide the desired product. MS (DCI) m/e 183 (M+H)⁺.

EXAMPLE 103D 2-methyl-2-(phenylsulfanyl)propylamine

The desired product was prepared by substituting Example 103C forExample 7A in Examples 7B and 7C.

EXAMPLE 103EN-((4′-fluoro(1,1′-biphenyl)-4-yl)carbonyl)-4-((2-methyl-2-(pheylsulfanyl)propyl)amino)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 103D forExample 7C in Example 7D. MS (ESI(−)) m/e 578 (M−H)⁻; ¹H NMR (400 MHz,DMSO-d₆) δ8.55 (m, 2H), 8.00 (d, 2H), 7.91 (d, 1H), 7.86 (dd, 1H), 7.78(m, 4H), 7.51-7.25 (m, 6H), 7.00 (m, 2H), 3.55 (s, 2H), 1.57 (s, 6H).

EXAMPLE 104N-((4′-fluoro(1,1′-biphenyl)-4-yl)carbonyl)-3-nitro-4-((1-(phenylsulfanyl)cycloheptyl)methoxy)benzenesulfonamideEXAMPLE 104A methyl 1-(phenylsulfanyl)cycloheptanecarboxylate

A −78° C. solution of Example 104A (911 mg, 5.0 mmol) and1,6-diiodohexane (845 mg, 2.5 mmol) in THF (70 mL) was treated with 1.0Msodium hexamethyldisilazide in THF (15 mL), warmed to room temperatureover 16 hours, diluted with hexanes (50 mL), filtered through a pad ofsilica gel, and concentrated. The concentrate was purified by flashcolumn chromatography on silica gel with 2-5% ethyl acetate/hexanes toprovide the desired product. MS (DCI) m/e 265 (M+H)⁺.

EXAMPLE 104B (1-(phenylsulfanyl)cycloheptyl)methanol

The desired product was prepared by substituting Example 104A forExample 103B in Example 103C. MS (DCI) m/e 237 (M+H)⁺.

EXAMPLE 104CN-((4′-fluoro(1,1′-biphenyl)-4-yl)carbonyl)-3-nitro-4-((1-(phenylsulfanyl)cycloheptyl)methoxy)benzenesulfonamide

A room temperature solution of Example 104B (117 mg 0.50 mmol) andExample 1D (100 mg, 0.23 mmol) in THF (3 mL) was treated with 60% sodiumhydride dispersion in oil (80 mg, 2.0 mmol), stirred for 16 hours,diluted with ethyl acetate (50 mL), washed sequentially with 1M HCl (5mL), water (5 mL), and brine (5 mL), dried (MgSO₄), filtered, andconcentrated. The concentrate was purified by flash columnchromatography on silica gel with 50% ethyl acetate/hexanes to providethe desired product. MS (ESI(−)) m/e 633 (M−H)⁻; ¹H NMR (400 MHz,DMSO-d₆) δ8.46 (d, 1H), 8.20 (dd, 1H), 8.00 (d, 2H), 7.97 (d, 2H), 7.79(m, 4H), 7.58 (d, 1H), 7.45 (m, 2H), 7.40-7.28 (m, 5H), 4.06 (s, 2H),1.90-1.50 (m, 12H).

EXAMPLE 1054-((1-adamantylmethyl)amino)-N-((2′-methoxy(1,1′-biphenyl)-4-yl)carbonyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 21A and Example28A for Example 1B and Example 1C, respectively, in Example 1D. MS(ESI(−)) m/e 574 (M−H)⁻; ¹H NMR (400 MHz, DMSO-d₆) δ8.67 (d, 1H), 8.59(t, 1H), 7.94 (dd, 1H), 7.89 (dt, 2H), 7.58 (dt, 2H), 7.39 (m, 2H), 7.31(dd, 1H), 7.24 (dd, 1H), 7.05 (dt, 1H), 3.76 (s, 3H), 3.19 (d, 2H),2.00-1.55 (m, 15H).

EXAMPLE 106N-((2′-methoxy(1,1′-biphenyl)-4-yl)carbonyl)-3-nitro-4-((2-(phenylsulfanyl)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 21A and Example77B for Example 1B and Example 1C, respectively, in Example 1D. MS(ESI(−)) m/e 562 (M−H)⁻; ¹H NMR (400 MHz, DMSO-d₆) δ8.79 (t, 1H), 8.52(d, 1H), 7.93 (dd, 1H), 7.89 (d, 2H), 7.58 (d, 2H), 7.40-7.00 (m, 10H),3.76 (s, 3H), 3.67 (q, 2H), 3.28 (t, 2H).

EXAMPLE 107N-((4′-fluoro(1,1′-biphenyl)-4-yl)carbonyl)-3-nitro-4-((2-(2-pyridinylsulfanyl)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting 2-pyridinethiol andExample 78A for thiophenol and Example 27A in Example 27B. MS (ESI(−))m/e 551 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ8.72 (t, 1H), 8.58 (d, 1H),8.51-8.47 (m, 1H), 8.01 (dd, 1H), 7.96 (d, 2H), 7.76 (dd, 2H), 7.69 (d,2H), 7.64 (td, 1H), 7.44 (d, 1H), 7.35-7.25 (m, 3H), 7.16-7.09 (m, 1H),3.72 (dt, 2H), 3.42 (t, 2H).

EXAMPLE 1083-nitro-N-(4-(1-oxo-2,3-dihydro-1H-inden-5-yl)benzoyl)-4-((2-(phenylsulfanyl)ethyl)amino)benzenesulfonamideEXAMPLE 108A3-nitro-4-((2-(phenylsulfanyl)ethyl)amino)-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl)benzenesulfonamide

The desired product was prepared by substituting Example 77B for Example3A in Example 3C. MS (ESI(−)) m/e 582 (M−H)⁻.

EXAMPLE 108B3-nitro-N-(4-(1-oxo-2,3-dihydro-1H-inden-5-yl)benzoyl)-4-((2-(phenylsulfanyl)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting 5-bromo-1-indanone andExample 108A for 4-bromo-1-iodobenzene and Example 3C, respectively, inExample 3D. MS (ESI(−)) m/e 586 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ8.51(d, 1H), 8.50 (t, 1H), 7.98 (m, 2H), 7.89 (m, 2H), 7.71 (m, 4H), 7.40(d, 2H), 7.31 (t, 2H), 7.20 (t, 2H), 6.98 (d, 1H), 3.60 (t, 2H), 3.27(t, 2H), 3.15 (t, 2H), 2.67 (t, 8H).

EXAMPLES 109-1 and 109-2N-(4-(3,4,4a,5,6,7,8,8a-octahydro-1-naphthalenyl)benzoyl)-3-nitro-4-((2-(phenylsulfanyl)ethyl)amino)benzenesulfonamideandN-(4-(2,3,4,4a,5,6,7,8-octahydro-1-naphthalenyl)benzoyl)-3-nitro-4-((2-(phenylsulfanyl)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting Example and Example 77Bfor Example 1B and Example 1C, respectively, in Example 1D. MS (ESI(−))m/e 590 (M−H)⁻; ¹H NMR (400 MHz, DMSO-d₆) δ8.77 (t, 1H), 8.60 (d, 1H),7.92 (dd, 1H), 7.80 (d, 2H), 7.36 (d, 2H), 7.40-7.15 (m, 6H), 5.80 (m,1H), 3.67 (q, 2H), 3.30 (t, 2H), 2.30-2.20 (m, 3H), 1.80-1.60 (m, 5H),1.40-1.20 (m, 6H).

EXAMPLE 110N-(4-(1,4,4a,5,6,7,8,8a-octahydro-2-naphthalenyl)benzoyl)-3-nitro-4-((2-(phenylsulfanyl)ethyl)amino)benzenesulfonamideandN-(4-(3,4,4a,5,6,7,8,8a-octahydro-2-naphthalenyl)benzoyl)-3-nitro-4-((2-(phenylsulfanyl)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 57A and Example78B for Example 5C and Example 3A, respectively, in Example 5D. MS(ESI(−)) m/e 590 (M−H)⁻; ¹H NMR (400 MHz, DMSO-d₆) δ8.77 (t, 1H), 8.60(d, 1H), 7.92 (dd, 1H), 7.82 (d, 2H), 7.50 (d, 2H), 7.40-7.15 (m, 6H),6.25 (m, 1H), 6.18 (m, 1H), 3.67 (q, 2H), 3.30 (t, 2H), 2.40 (m, 3H),1.70-1.20 (m, 12H).

EXAMPLE 111N-(4-decahydro-1-naphthalenylbenzoyl)-3-nitro-4-((2-(phenylsulfanyl)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 59A and Example77B for Example 5C and Example 3A, respectively, in Example 5D. MS(ESI(−)) m/e 592 (M−H)⁻; ¹H NMR (400 MHz, DMSO-d₆) δ8.77 (t, 1H), 8.60(d, 1H), 7.92 (dd, 1H), 7.78 (d, 2H), 7.45 (d, 1H), 7.37 (d, 2H),7.30-7.15 (m, 5H), 3.67 (q, 2H), 3.30 (t, 2H), 2.35 (m, 1H), 1.70-1.20(m, 16H).

EXAMPLE 112

The desired product was prepared by substituting Example 60A and Example77B for Example 5C and Example 3A, respectively, in Example 5D. MS(ESI(−)) m/e 592 (M−H)⁻; ¹H NMR (400 MHz, DMSO-d₆) δ8.77 (t, 1H), 8.60(d, 1H), 7.92 (dd, 1H), 7.80 (d, 2H), 7.45 (d, 1H), 7.37 (d, 2H),7.30-7.15 (m, 5H), 3.67 (q, 2H), 3.30 (t, 2H), 2.55 (m, 1H), 1.70-1.20(m, 16H).

EXAMPLE 1133-nitro-4-((2-(phenylsulfanyl)ethyl)amino)-N-(4-(5,6,7,8-tetrahydro-1-naphthalenyl)benzoyl)benzenesulfonamideEXAMPLE 113A methyl 4-(5,6,7,8-tetrahydro-1-naphthalenyl)benzoate

The desired product was prepared by substituting5,6,7,8-tetrahydro-1-naphthalenol for 4-tert-butylcyclohexanone inExamples 5A and 5B. MS (DCI) m/e 267 (M+H)⁺.

EXAMPLE 113B3-nitro-4-((2-(phenylsulfanyl)ethyl)amino)-N-(4-(5,6,7,8-tetrahydro-1-naphthalenyl)benzoyl)benzenesulfonamide

The desired product was prepared by substituting Example 113A andExample 77A for Example 5C and Example 3A, respectively, in Example 5D.MS (ESI(−)) m/e 586 (M−H)⁻; ¹H NMR (400 MHz, DMSO-d₆) δ8.77 (t, 1H),8.62 (d, 1H), 7.92 (dd, 1H), 7.90 (d, 2H), 7.40-7.18 (m, 10H), 6.95 (dd,1H), 3.67 (q, 2H), 3.30 (t, 2H), 2.80 (t, 2H), 2.49 (t, 2H), 1.75-1.60(m, 4H).

EXAMPLE 114A 1-bromo-4-fluoro-2-methoxybenzene

A mixture of 2-bromo-5-fluorophenol (2 mL, 17.8 mmol)), sodium hydride(0.5 g, 20.8 mmol) and iodomethane (5 mL, 82 mmol) in DMF (20 mL) washeated to 60° C., stirred for 16 hours, diluted with ethyl acetate (100mL), washed sequentially with 1M HCl, water, and brine, dried (MgSO₄),filtered, and concentrated to provide the desired product.

EXAMPLE 114B methyl 4′-fluoro-2′-methoxy(1,1′-biphenyl)-4-carboxylate

The desired product was prepared by substituting Example 114A forExample 5A in Example 5B. MS (DCI) m/e 262 (M+H)⁺.

EXAMPLE 114C4-((1-adamantyl)methylamino)-4′-fluoro(1,1′-biphenyl)-4-yl)carbonyl)-2′-methoxy-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 114B andExample 28A for Example 5C and Example 3A, respectively, in Example 5D.MS (ESI(−)) m/e 592 (M−H)⁻; ¹H NMR (400 MHz, DMSO-d₆) δ8.67 (d, 1H),8.56 (t, 1H), 7.92 (m, 3H), 7.52 (m, 2H), 7.33 (m, 2H), 7.05 (dd, 1H),6.86 (m, 1H), 3.59 (s, 3H), 3.18 (d, 2H), 2.46 (s, 6H), 1.98 (m, 3H),1.72-1.55 (m, 12H).

EXAMPLE 1154-((2-(phenylsulfanyl)ethyl)amino)-4′-fluoro(1,1′-biphenyl)-4-yl)carbonyl)-2′-methoxy-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 114B andExample 77B for Example 5C and Example 3A, respectively, in Example 5D.MS (ESI(−)) m/e 580 (M−H)⁻; ¹H NMR (400 MHz, DMSO-d₆) δ8.79 (t, 1H),8.52 (d, 1H), 7.93 (dd, 1H), 7.89 (d, 2H), 7.58 (d, 2H), 7.40-7.19 (m,7H), 7.05 (dd, 1H), 6.86 (m, 1H), 3.78 (s, 3H), 3.67 (q, 2H), 3.28 (t,2H).

EXAMPLE 1164-((2-(phenylsulfanyl)ethyl)amino)-4′-fluoro(1,1′-biphenyl)-4-yl)carbonyl)-2′-hydroxy-3-nitrobenzenesulfonamide

A −78° C. solution of Example 115 (20 mg, 5.0 mmol) in dichloromethane(1 mL) was treated with 1.0M boron tribromide in dichloromethane (0.2mL, 0.2 mmol), warmed to room temperature over 16 hours, diluted withmethanol (5 mL), and concentrated. The concentrate was purified by flashcolumn chromatography on silica gel with 50-100% ethyl acetate/hexanesto provide the desired product. MS (ESI(−)) m/e 566 (M−H)⁻; ¹H NMR (400MHz, DMSO-d₆) δ10.25 (s, 1H) 8.79 (t, 1H), 8.52 (d, 1H), 7.93 (dd, 1H),7.89 (d, 2H), 7.61 (d, 2H), 7.40-7.19 (m, 6H), 6.73 (m, 2H), 3.67 (q,2H), 3.28 (t, 2H).

EXAMPLE 1174-((2-(phenylsulfanyl)ethyl)amino)-(1,8′-quinoline)-4-yl)carbonyl)-2′-hydroxy-3-nitrobenzenesulfonamide

The desired product was prepared by substituting 8-bromoquinoline andExample 108A for 4-bromo-1-iodobenzene and Example 3C, respectively, inExample 3D. MS (ESI(−)) m/e 583 (M−H)⁻; ¹H NMR (400 MHz, DMSO-d₆) δ8.89(dd, 1H), 8.79 (t, 1H), 8.65 (d, 1H), 8.45 (dd, 1H), 8.05 (dd, 1H), 7.99(d, 2H), 7.83-7.70 (m, 4H), 7.59 (dd, 1H), 7.38 (d, 2H), 7.30-7.19 (m,4H), 3.69 (q, 2H), 3.28 (t, 2H).

EXAMPLE 1184-(((1R)-5-(dimethylamino)-1-((phenylthio)methyl)pentyl)amino)-N-((2′-methoxy-4′-(3-morpholin-4-ylpropyl)-1,1′-biphenyl-4-yl)carbonyl)-3-nitrobenzenesulfonamide

A solution of Example 194 (128 mg, 0.153 mmol) and 37% aqueousformaldehyde (0.15 mL) in 1:1 methanol/dichloromethane (4 mL) at roomtemperature was treated with MP-sodium cyanoborohydride (0.32 g, 0.767mmol (2.42 mmol/g) and stirred for 6 hours at room temperature. Theresin was filtered and washed with dichloromethane and the resultingsolution was concentrated. The concentrate was purified by reverse phasepreparative HPLC (using a C-18 column and a solvent system increasing ingradient from 10% to 100% acetonitrile/water containing 0.1% TFA) toprovide the desired product. MS (ESI(−)) m/e 788 (M−H)⁻; ¹H NMR (500MHz, DMSO-d₆) δ10.4 (br s, 1H), 9.5 (br s, 1H), 8.56 (d, 1H), 8.32 (d,1H), 7.92 (d, 2H), 7.90 (dd, 1H), 7.59 (d, 2H), 7.28-7.23 (m, 4H),7.17-7.09 (m, 3H), 7.01 (d, 1H), 6.93 (dd, 1H), 4.16-4.10 (m, 1H), 3.97(br s, 2H), 3.78 (s, 3H), 3.46 (br s, 2H), 3.41-3.33 (m, 2H), 3.16-3.12(m, 2H), 3.08 (br s, 2H), 2.99 (br s, 2H), 2.73 (s, 3H), 2.72 (s, 3H),2.69 (t, 2H), 2.06-2.01 (m, 2H), 1.82-1.76 (m, 2H), 1.60 (quint, 2H),1.39-1.32 (m, 2H).

EXAMPLE 119N-(4-(4,4-dimethylpiperidin-1-yl)benzoyl)-4-(((1R)-3-morpholin-4-yl-1-((phenylthio)methyl)propyl)amino)-3-nitrobenzenesulfonamideEXAMPLE 119A ethyl 4-(4,4-dimethyl-2,6-dioxopiperidin-1-yl)benzoate

A solution of ethyl 4-aminobenzoate (1.0 g, 6.1 mmol) and3,3-dimethylglutaric anhydride (0.95 g, 6.7 mmol) in 1,2-dichloroethane(15 mL) was heated to reflux for 1 hour, cooled to room temperature, andtreated dropwise with acetyl chloride (0.88 mL, 12.5 mmol). The mixturewas heated to reflux for 1 hour, cooled to room temperature, dilutedwith dichloromethane, washed sequentially with water, saturated NaHCO₃,and brine, dried (MgSO₄), filtered, and concentrated to provide thedesired product. MS(DCI(+)) m/e 290 (M+H)⁺.

EXAMPLE 119B ethyl 4-(4,4-dimethylpiperidin-1-yl)benzoate

Example 119A was processed according to the procedure described inLiebigs Ann. Chem. 1979, p. 461 to provide the desired product.MS(DCI(+)) m/e 262 (M+H)⁺.

EXAMPLE 119C 4-(4,4-dimethylpiperidin-1-yl)benzoic acid

A solution of Example 119B (260 mg, 1.0 mmol) and LiOH.H₂O (158 mg, 4.0mmol) in THF (19 mL), water (5 mL), and methanol (5 mL) was heated to75° C. for 18 hours, cooled to room temperature, concentrated, andadjusted to pH 3-4 with 1N HCl. The precipitate was collected byfiltration, washed with water, and dried under vacuum to provide thedesired product. MS(DCI(+)) m/e 234 (M+H)⁺.

EXAMPLE 119DN-(4-(4,4-dimethylpiperidin-1-yl)benzoyl)-4-(((1R)-3-morpholin-4-yl-1-((phenylthio)methyl)propyl)amino)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Examples 119C and 463Afor Examples 1B and 1C, respectively, in Example 1D. MS(ESI(+)) m/e 682(M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ8.52 (d, 1H), 8.40 (d, 1H), 7.82 (dd,1H), 7.72 (d, 2H), 7.28 (dd, 2H), 7.27-7.07 (m, 4H), 6.89 (d, 2H), 4.15(s, 1H), 3.54 (s, 4H), 3.30-3.25 (m, 6H), 2.50-2.32 (m, 6H), 1.95-1.82(m, 1H), 2.08-1.98 (m, 1H), 1.38 (t, 4H), 0.94 (s, 6H).

EXAMPLE 1204-(((1R)-5-amino-1-((phenylthio)methyl)pentyl)amino)-N-(4-(2-azaspiro(4.4)non-2-yl)benzoyl)-3-nitrobenzenesulfonamideEXAMPLE 120A methyl 4-(1,3-dioxo-2-azaspiro(4.4)non-2-yl)benzoate

The desired product was prepared by substituting methyl 4-aminobenzoateand 2-oxapiro(4.4)nonane-1,3-dione for ethyl-4-aminobenzoate and3,3-dimethylglutaric anhydride, respectively, in Example 119A.MS(DCI(+)) m/e 288 (M+H)⁺.

EXAMPLE 120B methyl 4-(2-azaspiro(4.4)non-2-yl)benzoate

The desired product was prepared by substituting Example 120A forExample 119A in Example 119B. MS(DCI(+)) m/e 260 (M+H)⁺.

EXAMPLE 120C 4-(2-azaspiro(4.4)non-2-yl)benzoic acid

The desired product was prepared by substituting Example 120B forExample 119B in Example 119C. MS(DCI(+)) m/e 246 (M+H)⁺.

EXAMPLE 120Dtert-butyl(5R)-5-((4-(((4-(2-azaspiro(4.4)non-2-yl)benzoyl)amino)sulfonyl)-2-nitrophenyl)amino)-6-(phenylthio)hexylcarbamate

The desired product was prepared by substituting Examples 120C and 124Cfor Examples 1B and 1C, respectively, in Example 1D. MS(ESI(−)) m/e 750(M−H)⁻.

EXAMPLE 120E4-(((1R)-5-amino-1-((phenylthio)methyl)pentyl)amino)-N-(4-(2-azaspiro(4.4)non-2-yl)benzoyl)-3-nitrobenzenesulfonamide

A solution of Example 120D (24 mg, 0.03 mmol) and 4N HCl (0.5 mL) indioxane at room temperature was stirred for 4 hours, partiallyconcentrated, and treated with diethyl ether. The precipitate wasfiltered, washed with diethyl ether, and was dried under vacuum toprovide the desired product. MS(ESI(+)) m/e 652 (M+H)⁺; ¹H NMR (300 MHz,DMSO-d₆) δ11.89 (s, 1H), 8.52 (d, 1H), 8.31 (d, 1H), 7.86 (dd, 1H), 7.74(d, 2H), 7.70 (s, 2H), 7.24-7.07 (m, 6H), 6.51 (d, 2H), 4.10 (m, 1H),3.57 (s, 4H), 3.35 (m, 4H), 3.18 (s, 2H), 2.74 (m, 2H), 1.86 (t, 2H),1.76 (m, 2H), 1.65 (m, 4H), 1.55 (t, 4H).

EXAMPLE 1214-(((1R)-3-(dimethylamino-1-((phenylthio)methyl)propyl)amino)-N-(4-(4,4-dimethylpiperidin-1-yl)benzoyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Examples 119C and 122Gfor Examples 1B and 1C, respectively, in Example 1D. MS(ESI(+)) m/e 640(M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ8.46 (d, 1H), 8.23 (d, 1H), 7.81 (dd,1H), 7.72 (d, 2H), 7.82-7.15 (m, 5H), 6.91 (d, 2H), 6.82 (d, 2H), 4.08(m, 1H), 3.35 (m, 2H), 3.21 (t, 4H), 2.9 (m, 2H), 2.56 (s, 6H), 2.04 (m,2H), 1.39 (t, 4H), 0.94 (s, 6H).

EXAMPLE 1224-(((1R)-3-(dimethylamino)-1-((phenylthio)methyl)propyl)amino)-N-((2′-methoxy-4′-(3-morpholin-4-ylpropyl)-1,1′-biphenyl-4-yl)carbonyl)-3-nitrobenzenesulfonamideEXAMPLE 122Atert-butyl(3R)-3-(((9H-fluoren-9-ylmethoxy)carbonyl)amino)-4-hydroxybutanoate

A solution of Fmoc-D-Asp(OtBu)-OH (9.0 g, 21.8 mmol) andN,N-diisopropylethylamine (4.6 mL) in THF (100 mL) at −40° C. wastreated with isobutyl chloroformate (3.1 mL, 24.1 mmol), warmed to 0° C.over 30 minutes, cooled to −20° C., and treated slowly with sodiumborohydride (1.64 g, 43.6 mmol) and methanol (10 mL). The reaction wasgradually warmed to room temperature over 2 hours, diluted with ethylacetate (200 mL), washed with water (100 mL) and brine (50 mL), dried(MgSO₄), filtered, and concentrated to provide the desired product. MS(ESI(+)) m/e 398 (M+H)⁺.

EXAMPLE 122Btert-butyl(3R)-3-(((9H-fluoren-9-ylmethoxy)carbonyl)amino)-4-(phenylthio)butanoate

The desired product was prepared by substituting Example 122A forExample 27A in Example 27B. MS (ESI(+)) m/e 490 (M+H)⁺.

EXAMPLE 122C 4-fluoro-3-nitrobenzenesulfonamide

A mixture of 2-fluoronitrobenzene (141 g, 1.0 mol) and chlorosulfonicacid (300 mL) was heated to 60° C. for 10 hours, cooled to roomtemperature, and slowly poured over ice (about 1 kg). The mixture wasextracted with ether (4 L) and the combined extracts were concentratedto a final volume of approximately 2 L. The solution was cooled to −40°C. and treated with concentrated ammonium hydroxide (300 mL) at such arate as to maintain an internal temperature of <10° C. The mixture wasseparated and the aqueous phase was extracted with ethyl acetate (2 L).The combined organic phase and extracts were washed with 4M HCl (300 mL)and brine (100 mL), dried (MgSO₄), filtered, and concentrated. Theconcentrate was crystallized from ethyl acetate/hexane to provide thedesired product. Concentration of the mother liquor and crystallizationof the concentrate provided additional product. MS (ESI(−)) m/e 219(M−H)⁻.

EXAMPLE 122D tert-butyl(3R)-3-((4-(aminosulfonyl)-2-nitrophenyl)amino)-4-(phenylthio)butanoate

A mixture of Example 122B (600 mg, 1.23 mmol), Example 122C (298 mg,1.34 mmol), and N,N-diisopropylethylamine (3 mL) in DMF (3 mL) at 60° C.was stirred for 12 hours, diluted with ethyl acetate (100 mL), washedwith water (45 mL) and brine (10 mL), dried (MgSO₄), filtered, andconcentrated. The concentrate was purified by flash columnchromatography on silica gel with 30% ethyl acetate/dichloromethane toprovide the desired product. MS (ESI(+)) m/e 468 (M+H)⁺.

EXAMPLE 122E(3R)-3-((4-(aminosulfonyl)-2-nitrophenyl)amino)-4-(phenylthio)butanoicacid

A mixture of Example 122D and 4M HCl in 1,4-dioxane (10 mL) was stirredat 50° C. for 5 hours and concentrated to provide the desired product.MS (ESI(+)) m/e 412 (M+H)⁺.

EXAMPLE 122F(3R)-3-((4-(aminosulfonyl)-2-nitrophenyl)amino)-N,N-dimethyl-4-(phenylthio)butanamide

A solution of Example 122E (411 mg, 1 mmol), 2M dimethylamine in THF (1mL), EDCI (296 mg, 1.5 mmol), and DMAP (10 mg) in DMF (10 mL) at roomtemperature was stirred for 16 hours, diluted with ethyl acetate (200mL), washed sequentially with 1N HCl (50 mL), water (50 mL), and brine(20 mL), dried (MgSO₄), filtered, and concentrated. The concentrate waspurified by flash column chromatography on silica gel with 100% ethylacetate to provide the desired product. MS (ESI(+)) m/e 439 (M+H)⁺.

EXAMPLE 122G4-(((1R)-3-(dimethylamino)-1-((phenylthio)methyl)propyl)amino)-3-nitrobenzenesulfonamide

A mixture of Example 122F (4.06 g, 9.25 mmol) and 1M borane in THF (20mL) at room temperature was stirred for 16 hours, treated with methanol(5.0 mL) and concentrated HCl (2 mL), stirred at 80° C. for 3 hours,cooled to room temperature, adjusted to pH>7 with 4M sodium carbonate,diluted with ethyl acetate (150 mL), washed with water (50 mL) and brine(10 mL), dried (MgSO₄), filtered, and concentrated. The concentrate waspurified by flash column chromatography on silica gel with 20%methanol/dichloromethane to provide the desired product. MS (ESI(+)) m/e425 (M+H)⁺.

EXAMPLE 122H 4-formyl-2-methoxyphenyl trifluoroacetate

A solution of vanillin (5.0 g, 32.9 mmol),N,N-phenyl(trifluoromethanesulfonimide (36 mmol), and triethylamine (36mmol) in dichloromethane (100 mL) was stirred at room temperatureovernight. The reaction mixture was diluted with ether (100 mL),filtered through silica gel (100 g), rinsed with a mixed solvent ofether/dichloromethane and concentrated. The concentrate was purified byflash column chromatography on silica gel with 10% ethyl acetate/hexanesto provide the desired product. MS (DCI) m/e 285 (M+H)⁺.

EXAMPLE 122I methyl 4′-formyl-2′-methoxy-1,1′-biphenyl-4-carboxylate

The desired product was prepared by substituting Example 122H forExample 5A in Example 5B. MS (DCI(+)) m/e 288 (M+H)⁺.

EXAMPLE 122J methyl4′-((1E)-3-tert-butoxy-3-oxoprop-1-enyl)-2′-methoxy-1,1′-biphenyl-4-carboxylate

A mixture of (tert-butoxycarbonylmethylene)triphenylphospharane (2.25 g,5.5 mmol) and Example 122I (1.35 g, 5.0 mmol) in THF (20 mL) at roomtemperature was stirred for 3 hours, diluted with hexanes (30 mL), andfiltered through silica gel (50 g). The silica gel was rinsed with 50%dichloromethane/ether and the combined solutions were concentrated toprovide the desired product. MS (ESI(−)) m/e 367 (M−H)⁻.

EXAMPLE 122K methyl4′-(3-tert-butoxy-3-oxopropyl)-2′-methoxy-1,1′-biphenyl-4-carboxylate

The desired product was prepared by substituting Example 122J forExample 5B in Example 5C. MS (ESI(−)) m/e 369 (M−H)⁻.

EXAMPLE 122L3-(2-methoxy-4′-(methoxycarbonyl)-1,1′-biphenyl-4-yl)propanoic acid

The desired product was prepared by substituting Example 122K forExample 122D in Example 122E.

EXAMPLE 122M methyl2′-methoxy-4′-(3-morpholin-4-yl-3-oxopropyl)-1,1′-biphenyl-4-carboxylate

A solution of Example 122L (500 mg, 1.59 mmol) in dichloromethane (5 mL)was treated with 2M oxalyl chloride in dichloromethane (1 mL) and a dropof DMF, stirred for 1 hour, concentrated under vacuum, and dissolved indichloromethane (5 mL). The mixture was treated with morpholine (0.5 mL)and the resulted slurry was filtered through silica gel (10 g). Thesilica gel was rinsed with ethyl acetate and concentrated. Theconcentrate was purified by flash column chromatography on silica gelwith 30% ethyl acetate/hexanes to provide the desired product. MS(ESI(+)) m/e 384 (M+H)⁺.

EXAMPLE 122N methyl2′-methoxy-4′-(3-morpholin-4-ylpropyl)-1,1′-biphenyl-4-carboxylate

The desired product was prepared by substituting Example 122M forExample 122F in Example 122G. MS (ESI(+)) m/e 369 (M+H)⁺.

EXAMPLE 122O2′-methoxy-4′-(3-morpholin-4-ylpropyl)-1,1′-biphenyl-4-carboxylic acid

The desired product was prepared by substituting Example 122N forExample 1A in Example 1B.

EXAMPLE 122P4-(((1R)-3-(dimethylamino)-1-((phenylthio)methyl)propyl)amino)-N-((2′-methoxy-4′-(3-morpholin-4-ylpropyl)-1,1′-biphenyl-4-yl)carbonyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Examples 122O and 122Gfor Example 1B and 1C, respectively, in Example 1D. MS (ESI(−)) m/e 760(M−H)⁻; ¹H NMR (500 MHz, CD₃OD) δ8.73 (d, 1H), 8.31 (d, 1H), 7.99 (dd,1H), 7.86 (d, 2H), 7.60 (d, 2H), 7.28-7.25 (m, 3H), 7.09 (m, 4H), 7.00(s, 1H), 6.94 (d, 1H), 4.22 (m, 1H), 4.03 (m, 2H), 3.81 (s, 3H), 3.74(t, 1H), 3.58 (t, 1H), 3.49 (m, 2H), 3.42 (dd, 1H), 3.25 (m, 3H), 3.18(m, 3H), 3.14 (m, 1H), 2.88 (s, 6H), 2.78 (t, 2H), 2.30 (m, 1H), 2.22(m, 1H), 2.14 (m, 2H).

EXAMPLE 1234-(((1R)-5-amino-1-((phenylthio)methyl)pentyl)amino)-N-(4-(4-ethyl-4-methylpiperidin-1-yl)benzoyl)-3-nitrobenzenesulfonamideEXAMPLE 123A methyl 4-(4-ethyl-4-methyl-2,6-dioxopiperidin-1-yl)benzoate

The desired product was prepared by substituting3-ethyl-3-methylglutaric anhydride and methyl 4-aminobenzoate for3,3-dimethylglutaric anhydride and ethyl 4-aminobenzoate, respectively,in Example 119A. MS(DCI(+)) m/e 290 (M+H)⁺.

EXAMPLE 123B methyl 4-(4-ethyl-4-methylpiperidin-1-yl)benzoate

The desired product was prepared by substituting Example 123A forExample 119A in Example 119B. MS(DCI(+)) m/e 262 (M+H)⁺.

EXAMPLE 123C 4-(4-ethyl-4-methylpiperidin-1-yl)benzoic acid

The desired product was prepared by substituting Example 123B forExample 119B in Example 119C. MS(DCI(+)) m/e 248 (M+H)⁺.

EXAMPLE 123D tert-butyl(5R)-5-((4-(((4-(4-ethyl-4-methylpiperidin-1-yl)benzoyl)amino)sulfonyl)-2-nitrophenyl)amino)-6-(phenylthio)hexylcarbamate

The desired product was prepared by substituting Examples 123C and 124Cfor Examples 1B and 1C, respectively, in Example 1D. MS (ESI(−)) m/e 752(M−H)⁻.

EXAMPLE 123E4-(((1R)-5-amino-1-((phenylthio)methyl)pentyl)amino)-N-(4-(4-ethyl-4-methylpiperidin-1-yl)benzoyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 123D forExample 120D in Example 120E. MS (ESI(−)) m/e 652 (M−H)⁻; ¹H NMR (300MHz, DMSO-d₆) δ12.0 (s, 1H), 8.54 (d, 1H), 8.31 (d, 1H), 7.86 (dd, 1H),7.75 (d, 2H), 7.10-7.25 (m, 6H), 6.94 (d, 2H), 6.82 (d, 2H), 4.10 (m,1H), 3.50 (m, 4H), 3.37 (m, 2H), 3.21 (m, 2H), 2.72 (m, 2H), 1.75 (m,2H), 1.52 (m, 2H), 1.38 (m, 4H), 1.29 (m, 2H), 0.90 (s, 3H), 0.80 (t,3H).

EXAMPLE 124N-(4-(8-azaspiro(4.5)dec-8-yl)benzoyl)-4-(((1R)-5-(dimethylamino)-1-((phenylthio)methyl)pentyl)amino)-3-nitrobenzenesulfonamideEXAMPLE 124A tert-butylN-((5R)-5-(((9H-fluoren-9-ylmethoxy)carbonyl)amino)-6-hydroxyhexyl)carbamate

A solution of Fmoc-D-Lys(BOC)—OH (2.102 g, 4.5 mmol) in DME (5 mL) at−15° C. was treated successively with N-methylmorpholine (0.56 mL, 5.0mmol) and isobutyl chloroformate (0.7 mL, 5 mmol), stirred for 2minutes, and filtered. The filter cake was washed with DME (3×5 mL) andthe combined filtrate and washings were cooled to −5° C. and treatedwith NaBH₄ (0.3 g, 7.5 mmol) in water (5 mL) and additional water(250mL) immediately afterwards. The mixture was stirred for 15 minutes andfiltered. The filter cake was washed with water and dried to provide thedesired product. MS (APCI) m/e 455 (M+H)⁺.

EXAMPLE 124B tert-butylN-((5R)-5-(((9H-fluoren-9-ylmethoxy)carbonyl)amino)-6-(phenylthio)hexyl)carbamate

A mixture of Example 124A (2.0 g, 4.4 mmol), PhSSPh (1.44 g, 6.6 mmol),and n-Bu₃P (1.65 mL, 6.6 mmol) in toluene (50 mL) at 80° C. was stirredfor 18 hours and concentrated. The concentrate was purified by flashcolumn chromatography on silica gel with 25% ethyl acetate/hexanes. MS(APCI) m/e 547 (M+H)⁺.

EXAMPLE 124C tert-butyl(5R)-5-((4-(aminosulfonyl)-2-nitrophenyl)amino)-6-(phenylthio)hexylcarbamate

A solution of Example 124B (0.65 g, 1.2 mmol), Example 122C (0.262 g,1.2 mmol), and diisopropylethylamine (0.5 mL) in DMSO (5 mL) at 50° C.was stirred for 18 hours, diluted with ethyl acetate (100 mL), washedwith water and brine, dried (Na₂SO₄), filtered, and concentrated. Theconcentrate was purified by flash column chromatography on silica gelwith 50% ethyl acetate/hexanes to provide the desired product. MS (ESI)m/e 523 (M−H)⁻.

EXAMPLE 124D 9H-fluoren-9-ylmethyl(1R)-5-(dimethylamino)-1-((phenylthio)methyl)pentylcarbamate

A solution of Example 124B (1.36 g, 2.4 mmol) in dichloromethane (5 mL)and TFA (5 mL) was stirred at room temperature for 30 minutes, andconcentrated. The concentrate was dissolved in acetic acid (1 mL) and37% aqueous formaldehyde (5 mL), treated with 1M NaCNBH₃ in THF (10 mL),stirred for 30 minutes, adjusted to pH 7 with aqueous NaHCO₃, andextracted with ethyl acetate(3×100 mL). The combined extracts werewashed with water and brine, dried (Na₂SO₄), filtered, and concentrated.The concentrate was purified by flash column chromatography on silicagel with 48:48:4 ethyl acetate/dichloromethane/methanol to provide thedesired product. MS (ESI) m/e 475 (M+H)⁺.

EXAMPLE 124E4-(((1R)-5-(dimethylamino)-1-((phenylthio)methyl)pentyl)amino)-3-nitrobenzenesulfonamide

A solution of Example 124D (1.2 g, 2.5 mmol), Example 122C (0.66 g, 3.0mmol), and diisopropylethylamine (1.0 mL) in DMSO (10 mL) was heated to50° C., stirred for 18 hours, diluted with ethyl acetate (100 mL),washed with water and brine, dried (Na₂SO₄), filtered, and concentrated.The concentrate was purified by flash column chromatography on silicagel with 50% ethyl acetate/dichloromethane to provide the desiredproduct. MS (ESI) m/e 453, 451 (M+H)⁺, (M−H)⁻.

EXAMPLE 124FN-(4-(8-azaspiro(4.5)dec-8-yl)benzoyl)-4-(((1R)-5-(dimethylamino)-1-((phenylthio)methyl)pentyl)amino)-3-nitrobenzenesulfonamide

A mixture of Example 124E (35 mg, 0.07 mmol), Example 257C (35 mg, 0.135mmol), EDCI (50 mg, 0.28 mmol), and DMAP (50 mg, 0.35 mmol) in t-butanol(0.5 mL) and 1,2-dichloroethane (0.5 mL) at room temperature was stirredfor 18 hours and concentrated. The concentrate was dissolved in 1:1DMSO/methanol (1 mL) and purified by preparative HPLC (using a C-18column and a solvent system increasing in gradient from 10-95%acetontrile/water containing 0.1% TFA). The purified product wasdissolved in 1:1 dichloromethane/methanol, treated with 2M HCl indiethyl ether (1 mL), and concentrated to provide the hydrochloridesalt. MS (ESI) m/e 694 (M+H)⁺, m/e 692 (M−H)⁻. ¹H NMR (500 MHz, DMSO-d₆)δ10.01 (m, 1H), 8.54 (d, 1H), 8.30 (d, 1H), 7.87 (dd, 1H), 7.75 (d, 2H),7.27-7.09 (m, 6H), 6.94 (d, 2H), 4.12 (m, 1H), 3.34 (m, 4H), 3.20 (d,2H), 2.95 (m, 2H), 2.69 (s, 3H), 2.68 (s, 3H), 1.78 (m, 2H), 1.60 (m,4H), 1.52-1.34 (m, 12H).

EXAMPLE 1254-((4-amino-1-((phenylthio)methyl)butyl)amino)-N-((4′-fluoro-1,1′-biphenyl-4-yl)carbonyl)-3-nitrobenzenesulfonamide

A mixture of Example 384E (53 mg), triphenylphosphine (131 mg), andwater (50 mg) in THF (3 mL) was heated to 60° C. for 24 hours, cooled toroom temperature, treated with 1M lithium hydroxide (2 mL), and stirredfor 48 hours. The mixture was treated with 4M HCl (1 mL) and silica gel(2.0 g) and concentrated. The concentrate was purified by flash columnchromatography on silica gel with 10-30% methanol/dichloromethane toprovide the desired product. MS (ESI(−)) m/e 607 (M−H)⁻; ¹H NMR (300MHz, DMSO-d₆) δ8.57 (d, 1H), 8.31 (d, 1H), 7.98 (d, 2H), 7.91 (dd, 1H),7.70 (m, 4H), 7.57 (m, 3H), 7.32 (m, 2H), 7.23 (dd, 2H), 7.13 (m, 4H),4.20 (m, 1H), 3.37 (m, 2H), 2.78 (m, 2H), 1.81 (m, 2H), 1.60 (m, 2H).

EXAMPLE 126(3R)-3-((4-((((2′-methoxy-4′-(3-(neopentylamino)-3-oxopropyl)-1,1′-biphenyl-4-yl)carbonyl)amino)sulfonyl)-2-nitrophenyl)amino)-N,N-dimethyl-4-(phenylthio)butanamideEXAMPLE 126A4′-(3-tert-butoxy-3-oxopropyl)-2′-methoxy-1,1′-biphenyl-4-carboxylicacid

A mixture of Example 122K (3.5 g), and potassium trimethylsilanolate(1.70 g) in THF (250 mL) at room temperature was stirred for 18 hours,diluted with ethyl acetate (400 mL) and water (50 mL), and adjusted topH 3 with 2N HCl. The organic phase was washed with water (150 mL) andbrine (100 mL), dried (MgSO₄), filtered, and concentrated to provide thedesired product. MS (DCI (+)) m/e 357 (M+H)⁺.

EXAMPLE 126B tert-butyl3-(4′-((((4-(((1R)-3-(dimethylamino)-3-oxo-1-((phenylthio)methyl)propyl)amino)-3-nitrophenyl)sulfonyl)amino)carbonyl)-2-methoxy-1,1′-biphenyl-4-yl)propanoate

A solution of Example 122F (2.7 g, 6.15 mmol), Example 126A (3.2 g, 9.2mmol), EDCI (2.349 g, 12.3 mmol), and DMAP (3.752 g, 30.75 mmol) in DMF(30 mL) and dichloroethane (30 mL) at room temperature was stirred for16 hours, diluted with ethyl acetate, washed with water and brine, dried(MgSO₄), filtered, and concentrated. The concentrate was purified byflash column chromatography on silica gel with 50% ethyl acetate/hexanesto provide the desired product. MS (ESI (−)) m/e 775 (M−H)⁻.

EXAMPLE 126C3-(4′-((((4-(((1R)-3-(dimethylamino)-3-oxo-1-((phenylthio)methyl)propyl)amino)-3-nitrophenyl)sulfonyl)amino)carbonyl)-2-methoxy-1,1′-biphenyl-4-yl)propanoicacid

A mixture of Example 126B in TFA (20 mL) and dichloromethane (20 mL) atroom temperature was stirred for 1 hour and concentrated to provide thedesired product. MS (ESI (+)) m/e 721 (M+H)⁺.

EXAMPLE 126D(3R)-3-((4-((((2′-methoxy-4′-(3-(neopentylamino)-3-oxopropyl)-1,1′-biphenyl-4-yl)carbonyl)amino)sulfonyl)-2-nitrophenyl)amino)-N,N-dimethyl-4-(phenylthio)butanamide

A solution of Example 126C (50 mg, 0.069 mmol), neopentylamine (21 mg,0.20 mmol), EDCI (20 mg, 0.104 mmol), and HOBT (15 mg, 0.104 mmol) inN,N-dimethylacetamide (1 mL) and dichloroethane (0.5 mL) at roomtemperature was stirred for 16 hours. The mixture was concentrated,dissolved in 1:1 DMSO/methanol (1.0 mL) and purified by reverse phasepreparative HPLC (using a C-18 column and a solvent system increasing ingradient from 20 to 95% acetonitrile/water containing 0.1% TFA) toprovide the desired product. MS (ESI(−)) m/e 788 (M−H)⁻; ¹H NMR (300MHz, DMSO-d₆) δ8.89 (br d, 1H), 8.57 (d, 1H), 7.90 (d, 2H), 7.85 (dd,1H), 7.70(br t, 1H), 7.58 (d, 2H), 7.30-7.12 (m, 7H), 7.00 (d, 1H), 6.90(dd, 1H), 4.45 (m, 1H), 3.75 (s, 3H), 3.42 (t, 2H), 2.90 (s, 3H), 2.79(s, 3H), 3.00-2.70 (m, 8H), 0.80 (s, 9H).

EXAMPLE 127(3R)-3-((4-((((4′-(3-hydroxypropyl)-2′-methoxy-1,1′-biphenyl-4-yl)carbonyl)amino)sulfonyl)-2-nitrophenyl)amino)-N,N-dimethyl-4-(phenylthio)butanamideEXAMPLE 127A(3R)-3-((4-((((4′-(3-((tert-butyl)dimethyl)silyl)oxy)propyl)-2′-methoxy-1,1′-biphenyl-4-yl)carbonyl)amino)sulfonyl)-2-nitrophenyl)amino)-N,N-dimethyl-4-(phenylthio)butanamide

The desired product was prepared by substituting Example 451B forExample 126A in Example 126B. MS (ESI(−)) m/e 803 (M−H)⁻.

EXAMPLE 127B(3R)-3-((4-((((4′-(3-hydroxypropyl)-2′-methoxy-1,1′-biphenyl-4-yl)carbonyl)amino)sulfonyl)-2-nitrophenyl)amino)-N,N-dimethyl-4-(phenylthio)butanamide

The desired product was prepared by substituting Example 127A forExample 126B in Example 126C. The mixture was concentrated, dissolved in1:1 DMSO/methanol (1 mL) and purified by reverse phase preparative HPLC(using a C-18 column and a solvent system increasing in gradient from20-95% acetonitrile/water containing 0.1% TFA). MS (ESI(−)) m/e 691(M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ8.89 (br d, 1H), 8.57 (d, 1H), 7.90(d, 2H), 7.85 (dd, 1H), 7.58 (d, 2H), 7.30-7.12 (m, 7H), 7.00 (d, 1H),6.89 (dd, 1H), 4.45 (m, 1H), 3.75 (s, 3H), 3.45 (m, 4H), 2.90 (s, 3H),2.79 (s, 3H), 3.10-2.70 (m, 2H), 2.65 (t, 2H), 1.75 (m, 2H).

EXAMPLE 128(3R)-3-((4-((((2′-methoxy-4′-(3-oxo-3-pyrrolidin-1-ylpropyl)-1,1′-biphenyl-4-yl)carbonyl)amino)sulfonyl)-2-nitrophenyl)amino)-N,N-dimethyl-4-(phenylthio)butanamide

The desired product was prepared by substituting pyrrolidine forneopentylamine in Example 126. MS (ESI(−)) m/e 772 (M−H)⁻; ¹H NMR (300MHz, DMSO-d₆) δ8.89 (br d, 1H), 8.57 (d, 1H), 7.90 (d, 2H), 7.85 (dd,1H), 7.58 (d, 2H), 7.30-7.12 (m, 7H), 7.02 (d, 1H), 6.92 (dd, 1H), 4.45(m, 1H), 3.75 (s, 3H), 3.42 (t, 2H), 3.28 (t, 2H), 2.90 (s, 3H), 2.79(s, 3H), 3.00-2.70 (m, 6H), 2.60 (t, 2H), 1.80 (m, 4H).

EXAMPLE 129(3R)-3-((4-((((2′-methoxy-4′-(3-oxo-3-(propylamino)propyl)-1,1′-biphenyl-4-yl)carbonyl)amino)sulfonyl)-2-nitrophenyl)amino)-N,N-dimethyl-4-(phenylthio)butanamide

The desired product was prepared by substituting propylaminehydrochloride for neopentylamine in Example 126 and addingN,N-diisopropylethylamine (0.1 mL) to the reaction mixture of Example126D. MS (ESI(−)) m/e 760 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ8.89 (br d,1H), 8.57 (d, 1H), 7.90 (d, 2H), 7.85 (dd, 1H), 7.81 (br t, 1H) 7.58 (d,2H), 7.30-7.12 (m, 7H), 7.00 (d, 1H), 6.90 (dd, 1H), 4.45 (m, 1H), 3.75(s, 3H), 3.42 (t, 2H), 2.90 (s, 3H), 2.79 (s, 3H), 3.00-2.70 (m, 6H),2.40 (t, 2H), 1.48 (m, 2H), 0.80 (t, 3H).

EXAMPLE 130(3R)-3-((4-((((2′-methoxy-4′-(3-oxo-3-piperidin-1-ylpropyl)-1,1′-biphenyl-4-yl)carbonyl)amino)sulfonyl)-2-nitrophenyl)amino)-N,N-dimethyl-4-(phenylthio)butanamide

The desired product was prepared by substituting piperidine forneopentylamine in Example 126. MS (ESI(−)) m/e 786 (M−H)⁻; ¹H NMR (300MHz, DMSO-d₆) δ8.89 (br d, 1H), 8.57 (d, 1H), 7.90 (d, 2H), 7.85 (dd,1H), 7.58 (d, 2H), 7.30-7.12 (m, 7H), 7.02 (d, 1H), 6.92 (dd, 1H), 4.45(m, 1H), 3.75 (s, 3H), 3.42 (t, 2H), 2.90 (s, 3H), 2.79 (s, 3H),3.00-2.70 (m, 6H), 2.60 (t, 2H), 2.50 (t, 2H), 1.60 (m, 2H), 1.48 (m,4H).

EXAMPLE 131 isobutyl4-(4-((((4-(((1R)-3-(dimethylamino)-1-((phenylthio)methyl)propyl)amino)-3-nitrophenyl)sulfonyl)amino)carbonyl)phenyl)piperazine-1-carboxylateEXAMPLE 131A isobutyl piperazine-1-carboxylate

A solution of piperazine (8.61 g, 0.1 mmol) in 1M HCl (200 mL) at roomtemperature was treated with isobutyl chloroformate (13.66 g, 13 mL, 0.1mol), adjusted to pH 3 with 1M NaOH over 1 to 2 hours, stirred for 18hours, quenched with 4M KOH, and extracted with dichloromethane (2×100mL). The combined extracts were dried (MgSO₄), filtered, andconcentrated to provide 10.9 g (59%) the desired product. MS (ESI(+))m/e 187 (M+H)⁺.

EXAMPLE 131B isobutyl4-(4-(ethoxycarbonyl)phenyl)piperazine-1-carboxylate

The mixture of ethyl 4-fluorobenzoate (4.88 g, 29 mmol, 4.3 mL), Example131A (5.4 g, 29 mmol), and potassium carbonate (4.007 g, 29 mmol) in NMP(10 mL) was heated to 140° C. for 18 hours, poured into water, andfiltered. The filter cake was washed with water and hexanes and driedunder vacuum at 50° C. to provide 2.8 g (29%) of the desired product. MS(ESI(+)) m/e 335 (M+H)⁺.

EXAMPLE 131C 4-(4-(isobutoxycarbonyl)piperazin-1-yl)benzoic acid

A solution of Example 131B (2.8 g, 8.37 mmol) and 4M aqueous NaOH (10mL) in 1:1 THF/methanol (40 mL) was heated to reflux for 18 hours, andconcentrated. The concentrate was diluted with water and adjusted to pH1 with concentrated HCl, treated with isobutyl chloroformate (3 mL),slowly adjusted to pH 12 with NaOH, and adjusted to pH 2 with HCl. Themixture was filtered and the filter cake was dried under vacuum toprovide the desired product. MS (ESI(−)) m/e 305 (M−H)⁻.

EXAMPLE 131D isobutyl4-(4-((((4-(((1R)-3-(dimethylamino)-1-((phenylthio)methyl)propylamino)-3-nitrophenyl)sulfonyl)amino)carbonyl)phenyl)piperazine-1-carboxylate

The desired product was prepared by substituting Example 131C andExample 122G for Example 1B and Example 1C, respectively, in Example 1D.MS (ESI(−)) m/e 711 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ8.46 (d, 1H),8.23 (d, 1H), 7.81 (dd, 1H), 7.75 (d, 2H), 7.34-7.30 (m, 2H), 7.28-7.21(m, 2H), 7.19-7.12 (m, 1H), 6.89 (d, 1H), 6.84 (d, 2H), 4.11-4.01 (m,1H), 3.81 (d, 2H), 3.54-3.46 (m, 4H), 3.33 (d, 2H), 3.21-3.17 (m, 4H),2.85-2.75 (m, 2H), 2.52 (s, 6H), 2.09-1.96 (m, 2H), 1.88 (hept, 1H),0.90 (d, 6H).

EXAMPLE 132(3R)-3-((4-((((2′-methoxy-4′-(3-oxo-3-((2,2,2-trifluoroethyl)amino)propyl)-1,1′-biphenyl-4-yl)carbonyl)amino)sulfonyl)-2-nitrophenyl)amino)-N,N-dimethyl-4-(phenylthio)butanamide

The desired product was prepared by substituting trifluoroethylaminehydrochloride for neopentylamine in Example 126 and also addingN,N-diisopropylethylamine (0.1 mL) to the reaction mixture in Example126D. MS (ESI(−)) m/e 800 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ8.89 (br d,1H), 8.57 (d, 1H), 8.52 (br t, 1H), 7.90 (d, 2H), 7.85 (dd, 1H), 7.58(d, 2H), 7.30-7.12 (m, 7H), 7.00 (d, 1H), 6.90 (dd, 1H), 4.45 (m, 1H),3.90 (m, 2H), 3.75 (s, 3H), 3.42 (t, 2H), 2.90 (s, 3H), 2.79 (s, 3H),3.00-2.70 (m, 4H), 2.60 (t, 2H).

EXAMPLE 133 methylN-(4-((((4′-(3-hydroxypropyl)-2′-methoxy-1,1′-biphenyl-4-yl)carbonyl)amino)sulfonyl)-2-nitrophenyl)-S-phenyl-L-cysteinateEXAMPLE 133A methyl N-(tert-butoxycarbonyl)-S-phenyl-L-cysteinate

A 0° C. solution of N-(tert-butoxycarbonyl)-L-serine methyl ester (30 g,137 mmol) and diisopropylamine (58 mL, 330 mmol) in dichloromethane (250mL) was treated with methanesulfonyl chloride (11.65 mL, 151 mmol),stirred for 20 minutes, treated with thiophenol (15.5 mL, 151 mmol),warmed to room temperature, stirred for 30 minutes, and concentrated.The concentrate was purified by flash column chromatography on silicagel with 10% ethyl acetate/hexanes to provide the desired product. MS(ESI(−)) m/e 310 (M−H)⁻.

EXAMPLE 133B methyl S-phenyl-L-cysteinate

A mixture of Example 133A in 1:1 dioxane/4M HCl at room temperature wasstirred for 3 hours, poured into saturated Na₂CO₃ (400 mL), andextracted with ethyl acetate (3×300 mL). The combined extracts weredried (Na₂SO₄), filtered, and concentrated to provide the desiredproduct.

EXAMPLE 133C methylN-(4-(aminosulfonyl)-2-nitrophenyl)-S-phenyl-L-cysteinate

The desired product was prepared by substituting Example 133B andExample 122C for 2,2-dimethylcyclopentylamine and Example 1D,respectively, in Example 1E. MS (ESI(−)) m/e 410 (M−H)⁻.

EXAMPLE 133D methylN-(4-((((4′-(3-hydroxypropyl)-2′-methoxy-1,1′-biphenyl-4-yl)carbonyl)amino)sulfonyl)-2-nitrophenyl)-S-phenyl-L-cysteinate

The desired product was prepared by substituting Example 133C andExample 451B for Example 1C and Example 1B, respectively, in Example 1D.The crude product was dissolved in TFA (5 mL), heated to 50° C. for 2hours, and concentrated. The concentrate was purified by flash columnchromatography on silica gel with ethyl acetate to provide the desiredproduct. ¹H NMR (300 MHz, DMSO-d₆) δ1.76 (tt, 2H), 2.65 (t, 2H), 3.43(t, 2H), 3.62 (s, 3H), 3.62 (m, 1H), 3.72 (m, 1H), 3.76 (s, 3H), 5.14(m, 1H), 6.88 (d, 1H), 6.96 (s, 1H), 7.10 (dd, 2H), 7.22 (d, 1H), 7.26(dd, 2H), 7.58 (dd, 2H), 7.88 (dd, 2H), 7.93 (dd, 1H), 8.58 (d, 1H),8.88 (d, 1H). MS (ESI(−)) m/e 678 (M−H)⁻.

EXAMPLE 134N-(4-(8-azaspiro(4.5)dec-8-yl)benzoyl)-4-(((1R)-2-(dimethylamino)-1-((phenylthio)methyl)ethyl)amino)-3-nitrobenzenesulfonamideEXAMPLE 134A tert-butyl (1R)-1-formyl-2-(phenylthio)ethylcarbamate

A solution of Example 133A (8.1 g, 26.0 mmol) in dichloromethane at −78°C. was treated with 1M DIBAL-H in dichloromethane (52 mL, 52 mmol),stirred for 3 hours, quenched with methanol (20 mL), and poured intosaturated NaH₂PO₄. The mixture was extracted with ethyl acetate (3×300mL), and the combined extracts were dried (Na₂SO₄), filtered,concentrated, and purified by flash column chromatography on silica gelwith 30% ethyl acetate/hexanes to provide the desired product. MS(ESI(−)) m/e 280 (M−H)⁻.

EXAMPLE 134B tert-butyl(1R)-2-(dimethylamino)-1-((phenylthio)methyl)ethylcarbamate

A solution of Example 134A (1.25 g, 4.44 mmol), 2M dimethylamine in THF(2.7 mL, 5.4 mmol), and NaBH(OAc)₃ (1.32 g, 6.22 mmol) indichloromethane at room temperature was stirred for 18 hours, andconcentrated. The concentrate was purified by flash columnchromatography on silica gel with 10% ethyl acetate/hexanes to providethe desired product. MS (ESI(+)) m/e 311 (M+H)⁺.

EXAMPLE 134C (2R)-N¹,N¹-dimethyl-3-(phenylthio)propane-1,2-diamine

The desired product was prepared by substituting Example 134B forExample 133A in Example 133B.

EXAMPLE 134D4-(((1R)-2-(dimethylamino)-1-((phenylthio)methyl)ethyl)amino)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 134C andExample 122C for 2,2-dimethylcyclopentylamine and Example 1D,respectively, in Example 1E. MS (ESI(−)) m/e 409 (M−H)⁻.

EXAMPLE 134EN-(4-(8-azaspiro(4.5)dec-8-yl)benzoyl)-4-(((1R)-2-(dimethylamino)-1-((phenylthio)methyl)ethyl)amino)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 134D andExample 257C for Example 1C and Example 1B, respectively, in Example 1D.MS (ESI(−)) m/e 650 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ1.41 (m, 4H),1.48 (m, 4H), 1.59(m, 4H), 2.31 (s, 6H), 2.63 (br s, 2H), 3.20 (m, 4H),3.28 (dd, 1H), 3.35 (dd, 1H), 4.13 (m, 1H), 6.81 (d, 2H), 6.95 (d, 1H),7.13 (dd, 1H), 7.21 (dd, 2H), 7.31 (d, 2H), 7.72 (d, 2H), 7.82 (dd, 1H),8.35 (d, 1H), 8.43 (s, 1H).

EXAMPLE 135(3R)-3-((4-((((2′-methoxy-4′-(3-oxo-3-((tetrahydrofuran-3-ylmethyl)amino)propyl)-1,1′-biphenyl-4-yl)carbonyl)amino)sulfonyl)-2-nitrophenyl)amino)-N,N-dimethyl-4-(phenylthio)butanamide

The desired product was prepared by substituting1-tetrahydrofuran-3-ylmethanamine for neopentylamine in Example 126. MS(ESI(−)) m/e 802 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ12.5 (br s, 1H),8.89 (br d, 1H), 8.57 (d, 1H), 7.92 (br t, 1H), 7.90 (d, 2H), 7.85 (dd,1H), 7.58 (d, 2H), 7.30-7.12 (m, 7H), 7.00 (d, 1H), 6.89 (dd, 1H), 4.45(m, 1H), 3.75 (s, 3H), 3.70-3.60(m, 4H), 3.42 (t, 2H), 2.90 (s, 3H),2.79 (s, 3H), 3.10-2.70 (m, 4H), 2.40 (t, 2H), 2.35(m, 1H), 1.85 (m,1H), 1.5 (m, 1H).

EXAMPLE 136(3R)-3-((4-((((2′-methoxy-4′-(3-oxo-3-(pentylamino)propyl)-1,1′-biphenyl-4-yl)carbonyl)amino)sulfonyl)-2-nitrophenyl)amino)-N,N-dimethyl-4-(phenylthio)butanamide

The desired product was prepared by substituting pentylamine forneopentylamine in Example 126. MS (ESI(−)) m/e 788 (M−H)⁻; ¹H NMR (300MHz, DMSO-d₆) δ12.5 (br s, 1H), 8.89 (br d, 1H), 8.57 (d, 1H), 7.90 (d,2H), 7.85 (dd, 1H), 7.80(br t, 1H), 7.58 (d, 2H), 7.30-7.12 (m, 7H),7.00 (d, 1H), 6.89 (dd, 1H), 4.45 (m, 1H), 3.75 (s, 3H), 3.42 (t, 2H),2.90 (s, 3H), 2.79 (s, 3H), 3.10-2.70 (m, 6H), 2.40 (t, 2H), 1.35(m,2H), 1.25 (m, 4H), 0.85 (t, 3H).

EXAMPLE 137(3R)-3-((4-((((4′-(2-(dimethylamino)-2-oxoethyl)-2′-methoxy-1,1′-biphenyl-4-yl)carbonyl)amino)sulfonyl)-2-nitrophenyl)amino)-N,N-dimethyl-4-(phenylthio)butanamide

The desired product was prepared by substituting Example 441A andExample 122F for Example 5C and Example 3A, respectively, in Example 5D.The mixture was concentrated, dissolved in 1:1 DMSO/methanol (1.0 mL)and purified by reverse phase preparative HPLC with 20-95%acetonitrile/water containing 0.1% TFA to provide the desired product.MS (ESI(−)) m/e 732 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ8.89 (br d, 1H),8.57 (d, 1H), 7.90 (d, 2H), 7.85 (dd, 1H), 7.58 (d, 2H), 7.30-7.12 (m,7H), 7.00 (d, 1H), 6.89 (dd, 1H), 4.45 (m, 1H), 3.75 (m, 5H), 3.45 (t,2H), 3.05 (s, 3H), 2.90 (s, 3H), 2.85 (s, 3H), 2.79 (s, 3H), 3.10 (m,2H).

EXAMPLE 138(3R)-3-((4-((((4′-(3-(4-acetylpiperazin-1-yl)-3-oxopropyl)-2′-methoxy-1,1′-biphenyl-4-yl)carbonyl)amino)sulfonyl)-2-nitrophenyl)amino)-N,N-dimethyl-4-(phenylthio)butanamide

The desired product was prepared by substituting 1-acetylpiperazine forneopentylamine in Example 126. MS (ESI(−)) m/e 829 (M−H)⁻. ¹H NMR (300MHz, DMSO-d₆) δ12.5 (br s, 1H), 8.89 (br d, 1H), 8.57 (d, 1H), 7.90 (d,2H), 7.85 (dd, 1H), 7.58 (d, 2H), 7.30-7.12 (m, 7H), 7.00 (d, 1H), 6.89(dd, 1H), 4.45 (m, 1H), 3.75 (s, 3H), 3.70-3.40 (m, 10H), 2.90 (s, 3H),2.79 (s, 3H), 3.10-2.70 (m, 6H), 2.00 (s, 3H).

EXAMPLE 139N-((5R)-5-((4-(((4-(8-azaspiro(4.5)dec-8-yl)benzoyl)amino)sulfonyl)-2-nitrophenyl)amino)-6-(phenylthio)hexyl)-1H-imidazole-1-carboxamide

A solution of Example 287 (200 mg, 0.3 mmol) and1,1′-carbonyldiimidazole (60 mg, 0.33 mmol) in THF(10 mL) was heated toreflux for 5 hours. The mixture was concentrated and the concentrate waspurified by flash column chromatography on silica gel with 1:1dichloromethane/ethyl acetate to provide the desired product. MS (ESI)m/e 760 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ9.46 (m, 1H), 8.48 (d, 1H),8.20 (m, 1H), 7.87 (dd, 1H), 7.73 (d, 2H), 7.62 (s, 1H), 7.28-6.98 (m,7H), 6.94 (d, 2H), 4.12 (m, 1H), 3.30-3.10 (m, 7H), 1.75 (m, 2H), 1.60(m, 4H), 1.52-1.34 (m, 12H).

EXAMPLE 140(3R)-3-((4-((((2′-methoxy-4′-(3-oxo-3-(tetrahydrofuran-2-ylmethyl)amino)propyl)-1,1′-biphenyl-4-yl)carbonyl)amino)sulfonyl)-2-nitrophenyl)amino)-N,N-dimethyl-4-(phenylthio)butanamide

The desired product was prepared by substituting1-tetrahydrofuran-2-ylmethanamine for neopentylamine in Example 126. MS(ESI(−)) m/e 802 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ12.3 (br s, 1H),8.89 (br d, 1H), 8.57 (d, 1H), 7,92 (br t, 1H), 7.90 (d, 2H), 7.85 (dd,1H), 7.58 (d, 2H), 7.30-7.12 (m, 7H), 7.00 (d, 1H), 6.89 (dd, 1H), 4.45(m, 1H), 3.75 (s, 3H), 3.70-3.40 (m, 3H), 3.45 (t, 2H), 3.10 (t, 2H),2.90 (s, 3H), 2.79 (s, 3H), 3.10-2.70 (m, 4H), 2.48 (t, 2H), 1.75 (m,3H), 1.45 (m, 1H).

EXAMPLE 141(3R)-3-((4-((((4′-(3-amino-3-oxopropyl)-2′-methoxy-1,1′-biphenyl-4-yl)carbonyl)amino)sulfonyl)-2-nitrophenyl)amino)-N,N-dimethyl-4-(phenylthio)butanamide

The desired product was prepared by substituting ammonium chloride forneopentylamine in Example 126 and adding N,N-diisopropylethylamine (0.1mL) to the reaction mixture in Example 126D. MS (ESI(−)) m/e 718 (M−H)⁻;¹H NMR (300 MHz, DMSO-d₆) δ12.4 (br s, 1H), 8.89 (br d, 1H), 8.57 (d,1H), 7.90 (d, 2H), 7.85 (dd, 1H), 7.58 (d, 2H), 7.30-7.12 (m, 7H), 7.00(d, 1H), 6.89 (dd, 1H), 6.80 (br s, 2H), 4.45 (m, 1H), 3.75 (s, 3H),3.40 (t, 2H), 2.90 (s, 3H), 2.79 (s, 3H), 3.10-2.70 (m, 4H), 2.42 (t,H).

EXAMPLE 142(3R)-3-((4-((((4′-(3-(cyclobutylamino)-3-oxopropyl)-2′-methoxy-1,1′-biphenyl-4-yl)carbonyl)amino)sulfonyl)-2-nitrophenyl)amino)-N,N-dimethyl-4-(phenylthio)butanamide

The desired product was prepared by substituting cyclobutylamine forneopentylamine in Example 126. MS (ESI(−)) m/e 772 (M−H)⁻; ¹H NMR (300MHz, DMSO-d₆) δ12.4 (br s, 1H), 8.89 (br d, 1H), 8.57 (d, 1H), 8.05 (brd, 1H), 7.90 (d, 2H), 7.85 (dd, 1H), 7.58 (d, 2H), 7.30-7.12 (m, 7H),7.00 (d, 1H), 6.89 (dd, 1H), 4.45 (m, 1H), 4.20 (m, 1H), 3.75 (s, 3H),3.45 (t, 2H), 2.90 (s, 3H), 2.79 (s, 3H), 3.10-2.70 (m, 4H), 2.45 (t,2H), 2.12 (m, 2H), 1.82 (m, 2H), 1.62 (m, 2H).

EXAMPLE 143(3R)-3-((4-((((4′-(3-(tert-butylamino)-3-oxopropyl)-2′-methoxy-1,1′-biphenyl-4-yl)carbonyl)amino)sulfonyl)-2-nitrophenyl)amino)-N,N-dimethyl-4-(phenylthio)butanamide

The desired product was prepared by substituting tert-butylamine forneopentylamine in Example 126. MS (ESI(−)) m/e 774 (M−H)⁻; ¹H NMR (300MHz, DMSO-d₆) δ12.4 (br s, 1H), 8.89 (br d, 1H), 8.57 (d, 1H), 7.90 (d,2H), 7.85 (dd, 1H), 7.58 (d, 2H), 7.42 (br s, 1H), 7.30-7.12 (m, 7H),7.00 (d, 1H), 6.89 (dd, 1H), 4.45 (m, 1H), 3.75 (s, 3H), 3.45 (t, 2H),2.90 (s, 3H), 2.79 (s, 3H), 3.10-2.70 (m, 4H), 2.45 (t, 2H), 1.25 (s,9H).

EXAMPLE 144(3R)-3-((4-((((2′-methoxy-4′-(3-(methylamino)-3-oxopropyl)-1,1′-biphenyl-4-yl)carbonyl)amino)sulfonyl)-2-nitrophenyl)amino)-N,N-dimethyl-4-(phenylthio)butanamide

The desired product was prepared by substituting methylaminehydrochloride for neopentylamine in Example 126 and addingN,N-diisopropylethylamine (0.1 mL) to the reaction mixture in Example126D. MS (ESI(−)) m/e 732 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ8.89 (br d,1H), 8.57 (d, 1H), 7.90 (d, 2H), 7.85 (dd, 1H), 7.78 (br q, 1H), 7.58(d, 2H), 7.30-7.12 (m, 7H), 7.00 (d, 1H), 6.89 (dd, 1H), 4.45 (m, 1H),3.75 (s, 3H), 3.45 (t, 2H), 2.90 (s, 3H), 2.79 (s, 3H), 3.10-2.70 (m,4H), 2.52 (d, 3H), 2.45 (t, 2H).

EXAMPLE 145(3R)-3-((4-((((2′-methoxy-4′-(3-((2-(2-methoxyethoxy)ethyl)amino)-3-oxopropyl)-1,1′-biphenyl-4-yl)carbonyl)amino)sulfonyl)-2-nitrophenyl)amino)-N,N-dimethyl-4-(phenylthio)butanamide

The desired product was prepared by substituting2-(2-methoxyethoxy)ethylamine hydrochloride for neopentylamine inExample 126 and adding N,N-diisopropylethylamine (0.1 mL) to thereaction mixture in Example 126D. MS (ESI(−)) m/e 820 (M−H)⁻; ¹H NMR(300 MHz, DMSO-d₆) δ8.89 (br d, 1H), 8.57 (d, 1H), 7.92 (br t, 1H), 7.90(d, 2H), 7.85 (dd, 1H), 7.58 (d, 2H), 7.30-7.12 (m, 7H), 7.00 (d, 1H),6.89 (dd, 1H), 4.45 (m, 1H), 3.75 (s, 3H), 3.50-3.45 (m, 8H), 3.26 (s,3H), 3.20 (t, 2H), 2.90 (s, 3H), 2.79 (s, 3H), 3.10-2.70 (m, 4H), 2.45(t, 2H).

EXAMPLE 146N-(4-(8-azaspiro(4.5)dec-8-yl)benzoyl)-4-(((1R)-2-morpholin-4-yl-1-((phenylthio)methyl)ethyl)amino)-3-nitrobenzenesulfonamideEXAMPLE 146Atert-butyl(1R)-2-morpholin-4-yl-1-((phenylthio)methyl)ethylcarbamate

The desired product was prepared by substituting morpholine fordimethylamine in Example 134B. MS (ESI(−)) m/e 351 (M−H)⁻.

EXAMPLE 146B (2R)-1-morpholin-4-yl-3-(phenylthio)propan-2-amine

The desired product was prepared by substituting Example 146A forExample 133A in Example 133B.

EXAMPLE 146C4-(((1R)-2-morpholin-4-yl-1-((phenylthio)methyl)ethyl)amino)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 146B andExample 122C for 2,2-dimethylcyclopentylamine and Example 1D,respectively, in Example 1E. MS (ESI(−)) m/e 451 (M−H)⁻.

EXAMPLE 146DN-(4-(8-azaspiro(4.5)dec-8-yl)benzoyl)-4-(((1R)-2-morpholin-4-yl-1-((phenylthio)methyl)ethyl)amino)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 146C andExample 257C for Example 1C and Example 1B, respectively, in Example 1D.MS (ESI(−)) m/e 692 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ1.41 (m, 4H),1.48 (m, 4H), 1.59(m, 4H), 2.38 (m, 2H), 2.42 (m, 2H), 2.61 (d, 2H),3.25 (m, 4H), 3.28 (dd, 1H), 3.42 (dd, 1H), 3.51 (m, 4H), 4.18 (m, 1H),6.85 (d, 2H), 7.05 (d, 1H), 7.11 (dd, 1H), 7.19 (dd, 2H), 7.31 (d, 2H),7.71 (d, 2H), 7.83 (dd, 1H), 8.40 (d, 1H), 8.48 (s, 1H).

EXAMPLE 147 methylN-(4-((((4′-(3-(dimethylamino)-3-oxopropyl)-2′-methoxy-1,1′-biphenyl-4-yl)carbonyl)amino)sulfonyl)-2-nitrophenyl)-S-phenyl-L-cysteinateEXAMPLE 147A4′-(3-(dimethylamino)-3-oxopropyl)-2′-methoxy-1,1′-biphenyl-4-carboxylicacid

The desired product was prepared by substituting Example 427A forExample 1A in Example 1B.

EXAMPLE 147B methylN-(4-((((4′-(3-(dimethylamino)-3-oxopropyl)-2′-methoxy-1,1′-biphenyl-4-yl)carbonyl)amino)sulfonyl)-2-nitrophenyl)-S-phenyl-L-cysteinate

The desired product was prepared by substituting Example 147A andExample 133C for Example 1B and Example 1C, respectively, in Example 1D.MS (ESI(−)) m/e 719 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ2.64 (t, 2H),2.82 (t, 2H), 2.82 (s, 3H), 2.95 (s, 3H), 3.61 (s, 3H), 3.72 (m, 1H),3.75 (m, 1H), 3.76 (s, 3H), 5.11 (m, 1H), 6.90 (d, 1H), 7.01 (s, 1H),7.11 (m, 2H), 7.21 (d, 1H), 7.26 (dd, 2H), 7.53 (dd, 2H), 7.89 (dd, 2H),7.93 (dd, 1H), 8.55 (d, 1H), 8.81 (d, 1H).

EXAMPLE 148N-(4-(8-azaspiro(4.5)dec-8-yl)benzoyl)-4-(((1R)-2-(4-methylpiperazin-1-yl)-1-((phenylthio)methyl)ethyl)amino)-3-nitrobenzenesulfonamideEXAMPLE 148A tert-butyl(1R)-2-(4-methylpiperazin-1-yl)-1-((phenylthio)methyl)ethylcarbamate

The desired product was prepared by substituting N-methylpiperazine fordimethylamine in Example 134B. MS (ESI(+)) m/e 366 (M+H)⁺.

EXAMPLE 148B(2R)-1-(4-methylpiperazin-1-yl)-3-(phenylthio)propan-2-amine

The desired product was prepared by substituting Example 148A forExample 133A in Example 133B.

EXAMPLE 148C4-(((1R)-2-(4-methylpiperazin-1-yl)-1-((phenylthio)methyl)ethyl)amino)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 148B andExample 122C for 2,2-dimethylcyclopentylamine and Example 1D,respectively, in Example 1E. MS (ESI(−)) m/e 464 (M−H)⁻.

EXAMPLE 148DN-(4-(8-azaspiro(4.5)dec-8-yl)benzoyl)-4-(((1R)-2-(4-methylpiperazin-1-yl)-1-((phenylthio)methyl)ethyl)amino)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 148C andExample 257C for Example 1C and Example 1B, respectively, in Example 1D.MS (ESI(−)) m/e 705 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ1.42 (m, 4H),1.49 (m, 4H), 1.59 (m, 4H), 2.42 (s, 3H), 3.20(m, 4H), 3.22-3.40 (m,12H), 4.12 (m, 1H), 6.80 (d, 2H), 6.95 (d, 1H), 7.16 (dd, 1H), 7.23 (dd,2H), 7.31 (d, 2H), 7.71 (d, 2H), 7.81 (dd, 1H), 8.30 (d, 1H), 8.44 (s,1H).

EXAMPLE 1494-(((1R)-3-(dimethylamino)-1-((phenylthio)methyl)propyl)amino)-N-((2′-methoxy-4′-(3-(4-methylpiperazin-1-yl)-3-oxopropyl)-1,1′-biphenyl-4-yl)carbonyl)-3-nitrobenzenesulfonamideEXAMPLE 149A2′-methoxy-4′-(3-(4-methylpiperazin-1-yl)-3-oxopropyl)-1,1′-biphenyl-4-carboxylicacid

The desired product was prepared by substituting Example 362A forExample 1A in Example 1B.

EXAMPLE 149B4-(((1R)-3-(dimethylamino)-1-((phenylthio)methyl)propyl)amino)-N-((2′-methoxy-4′-(3-(4-methylpiperazin-1-yl)-3-oxopropyl)-1,1′-biphenyl-4-yl)carbonyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 149A andExample 122G for Example 1B and Example 1C, respectively, in Example 1D.MS (ESI) m/e 787, 789 (M−H)⁻, (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ2.05(m, 2H), 2.20 (s, 3H), 2.28 (t, 4H), 2.56 (s, 6H), 2.66 (t, 2H), 2.84(t, 2H), 3.28 (d, 2H), 3.41 (m, 2H), 3.46 (t, 4H), 3.74 (s, 3H), 4.08(m, 1H), 6.89 (t, 2H), 6.98 (s, 1H), 7.16 (d, 1H), 7.18 (d, 1H), 7.25(t, 2H), 7.32 (d, 2H), 7.38 (d, 2H), 7.82 (dd, 1H), 7.88 (d, 2H), 8.21(d, 1H), 8.48 (d, 1H).

EXAMPLE 150(3R)-3-((4-((((4′-(3-azetidin-1-yl-3-oxopropyl)-2′-methoxy-1,1′-biphenyl-4-yl)carbonyl)amino)sulfonyl)-2-nitrophenyl)amino)-N,N-dimethyl-4-(phenylthio)butanamide

The desired product was prepared by substituting azetidine hydrochloridefor neopentylamine in Example 126 and adding N,N-diisopropylethylamine(0.1 mL) to the reaction mixture in Example 126D. MS (ESI(−)) m/e 758(M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ8.89 (br d, 1H), 8.57 (d, 1H), 7.90(d, 2H), 7.85 (dd, 1H), 7.58 (d, 2H), 7.30-7.12 (m, 7H), 7.00 (d, 1H),6.89 (dd, 1H), 4.45 (m, 1H), 4.05 (t, 2H), 3.82 (t, 2H), 3.75 (s, 3H),3.45 (t, 2H), 2.90 (s, 3H), 2.79 (s, 3H), 3.10-2.70 (m, 4H), 2.35 (t,2H).

EXAMPLE 151(3R)-3-((4-((((4′-(3-(isopropylamino)-3-oxopropyl)-2′-methoxy-1,1′-biphenyl-4-yl)carbonyl)amino)sulfonyl)-2-nitrophenyl)amino)-N,N-dimethyl-4-(phenylthio)butanamide

The desired product was prepared by substituting isopropylamine forneopentylamine in Example 126. MS (ESI(−)) m/e 760 (M−H)⁻; ¹H N (300MHz, DMSO-d₆) δ8.89 (br d, 1H), 8.57 (d, 1H), 7.90 (d, 2H), 7.85 (dd,1H), 7.60 (br d, 1H), 7.58 (d, 2H), 7.30-7.12 (m, 7H), 7.00 (d, 1H),6.89 (dd, 1H), 4.45 (m, 1H), 3.85 (m, 1H), 3.75 (s, 3H), 3.45 (t, 2H),2.90 (s, 3H), 2.79 (s, 3H), 3.10-2.70 (m, 4H), 2.45 (t, 2H), 1.02 (d,6H).

EXAMPLE 152(3R)-3-((4-((((2′-methoxy-4′-(3-(methyl(propyl)amino)-3-oxopropyl)-1,1′-biphenyl-4-yl)carbonyl)amino)sulfonyl)-2-nitrophenyl)amino)-N,N-dimethyl-4-(phepylthio)butanamide

The desired product was prepared by substituting N-methyl-N-propylaminefor neopentylamine in Example 126. MS (ESI(−)) m/e 774 (M−H)⁺; ¹H NMR(300 MHz, DMSO-d₆) δ8.89 (br d, 1H), 8.57 (d, 1H), 7.90 (d, 2H), 7.85(dd, 1H), 7.58 (d, 2H), 7.30-7.12 (m, 7H), 7.00 (d, 1H), 6.89 (dd, 1H),4.45 (m, 1H), 3.75 (s, 3H), 3.45 (t, 2H), 3.25 (t, 2H), 2.95 (s, 3H),2.90 (s, 3H), 2.79 (s, 3H), 3.10-2.70 (m, 4H), 2.65 (t, 2H), 1.50 (m,9H), 0.85 (t, 3H).

EXAMPLE 153(3R)-3-((4-((((4′-(3-((2-(dimethylamino)ethyl)amino)-3-oxopropyl)-2′-methoxy-1,1′-biphenyl-4-yl)carbonyl)amino)sulfonyl)-2-nitrophenyl)amino)-N,N-dimethyl-4-(phenylthio)butanamide

The desired product was prepared by substitutingN,N-dimethylethylenediamine for neopentylamine in Example 126. MS(ESI(−)) m/e 789 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ9.25 (br s, 1H),8.89 (br d, 1H), 8.57 (d, 1H), 8.12 (br t, 1H), 7.90 (d, 2H), 7.85 (dd,1H), 7.58 (d, 2H), 7.30-7.12 (m, 7H), 7.00 (d, 1H), 6.89 (dd, 1H), 4.45(m, 1H), 3.75 (s, 3H), 3.45 (m, 6H), 3.15 (t, 2H), 2.95 (s, 3H), 2.80(s, 3H), 2.79 (s, 6H), 3.10-2.70 (m, 4H).

EXAMPLE 154(3R)-3-((4-((((4′-(3-((2-(dimethylamino)ethyl)(methyl)amino)-3-oxopropyl)-2′-methoxy-1,1′-biphenyl-4-yl)carbonyl)amino)sulfonyl)-2-nitrophenyl)amino)-N,N-dimethyl-4-(phenylthio)butanamide

The desired product was prepared by substitutingN,N,N′-trimethylethylenediamine for neopentylamine in Example 126. MS(ESI(−)) m/e 803 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ9.25 (br s, 1H),8.89 (br d, 1H), 8.57 (d, 1H), 7.90 (d, 2H), 7.85 (dd, 1H), 7.58 (d,2H), 7.30-7.12 (m, 7H), 7.00 (d, 1H), 6.89 (dd, 1H), 4.45 (m, 1H), 3.75(s, 3H), 3.65 (m, 4H), 3.45 (t, 2H), 3.15 (t, 2H), 2.95 (s, 3H), 2.90(s, 3H), 2.82 (s, 6H), 2.79 (s, 3H), 3.10-2.70 (m, 4H).

EXAMPLE 155(3R)-3-((4-((((4′-(3-(tert-butyl(methyl)amino)-3-oxopropyl)-2′-methoxy-1,1′-biphenyl-4-yl)carbonyl)amino)sulfonyl)-2-nitrophenyl)amino)-N,N-dimethyl-4-(phenylthio)butanamide

The desired product was prepared by substitutingN-methyl-tert-butylamine for neopentylamine in Example 126. MS (ESI(−))m/e 788 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ8.89 (br d, 1H), 8.57 (d,1H), 7.90 (d, 2H), 7.85 (dd, 1H), 7.58 (d, 2H), 7.30-7.12 (m, 7H), 7.00(d, 1H), 6.89 (dd, 1H), 4.45 (m, 1H), 3.75 (s, 3H), 3.45 (t, 2H), 2.95(s, 3H), 2.85 (s, 3H), 2.79 (s, 3H), 3.10-2.70 (m, 4H), 2.60 (t, 2H),1.35 (s, 9H).

EXAMPLE 156 isobutyl4-(4-((((4-(((1R)-5-amino-1-((phenylthio)methyl)penthyl)amino)-3-nitrophenyl)sulfonyl)amino)carbonyl)phenyl)piperazine-1-carboxylateEXAMPLE 156A isobutyl4-(4-((((4-(((1R)-5-((tert-butoxycarbonyl)amino)-1-((phenylthio)methyl)pentyl)amino)-3-nitrophenyl)sulfonyl)amino)carbonyl)phenyl)piperazine-1-carboxylate

The desired product was prepared by substituting Example 131C andExample 124C for Example 1B and Example 1C, respectively, in Example 1D.

EXAMPLE 156B isobutyl4-(4-((((4-(((1R)-5-amino-1-((phenylthio)methyl)pentyl)amino)-3-nitrophenyl)sulfonyl)amino)carbonyl)phenyl)piperazine-1-carboxylate

The desired product was prepared by substituting Example 156A forExample 120D in Example 120E. MS (ESI(−)) m/e 711 (M−H)⁻; ¹H NMR (300MHz, DMSO-d₆) δ12.07 (br S, 1H), 8.54 (d, 1H), 8.32 (d, 1H), 7.86 (dd,1H), 7.78 (d, 2H), 7.76 (br s, 1H), 7.26-7.08 (m, 6H), 6.96 (d, 1H),4.12-4.01 (m, 1H), 3.81 (d, 2H), 3.74-3.65 (m, 2H), 3.54-3.46 (m, 4H),3.38-3.34 (m, 4H), 2.78-2.70 (m, 2H), 1.88 (hept, 1H), 1.8-1.72 (m, 2H),1.56-1.47 (m, 2H), 1.45-1.35 (m, 2H), 0.90 (d, 6H).

EXAMPLE 157(3R)-3-((4-((((4′-(3-(diethylamino)-3-oxopropyl)-2′-methoxy-1,1′-biphenyl-4-yl)carbonyl)amino)sulfonyl)-2-nitrophenyl)amino)-N,N-dimethyl-4-(phenylthio)butanamide

The desired product was prepared by substituting diethylaminehydrochloride for neopentylamine in Example 126 and addingN,N-diisopropylethylamine (0.1 mL) to the reaction mixture in Example126D. MS (ESI(−)) m/e 774 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ8.89 (br d,1H), 8.57 (d, 1H), 7.90 (d, 2H), 7.85 (dd, 1H), 7.58 (d, 2H), 7.30-7.12(m, 7H), 7.00 (d, 1H), 6.89 (dd, 1H), 4.45 (m, 1H), 3.75 (s, 3H), 3.45(t, 2H), 3.30 (m, 4H), 2.90 (s, 3H), 2.79 (s, 3H), 3.10-2.70 (m, 4H),2.60 (t, 2H), 1.05 (2t, 6H).

EXAMPLE 1584-(((1R)-5-amino-1-((phenylthio)methyl)pentyl)amino)-N-(4-(6-azaspiro(2.5)oct-6-yl)benzoyl)-3-nitrobenzenesulfonamideEXAMPLE 158A ethyl 4-(1,4-dioxa-8-azaspiro(4.5)dec-8-yl)benzoate

A mixture of ethyl 4-fluorobenzoate (6.0 mL, 41 mmol),1,4-dioxa-8-azaspiro(4,5)decane (13.5 mL, 102 mmol), and K₂CO₃ (5.7 g,41 mmol) in NMP (35 mL) was stirred at 150° C. for 4 hours, cooled toroom temperature, treated with water (0.5 L) and filtered. The filtercake was washed with water and dried briefly. The crude product wastriturated with hexane, filtered, and dried under vacuum to provide thedesired product. MS (DCI) m/e 292 (M+H)⁺.

EXAMPLE 158B ethyl 4-(4-oxopiperidin-1-yl)benzoate

A solution of Example 158A (6.31 g, 21.7 mmol) and 30% aqueous aceticacid (100 mL) in THF (50 mL) was stirred at 95° C. for 6 hours, cooledto room temperature, concentrated, treated with water, and extractedwith dichloromethane. The combined extracts were washed with water andbrine, dried (MgSO₄), filtered, and concentrated to provide the desiredproduct. MS (DCI) m/e 248 (M+H)⁺.

EXAMPLE 158C ethyl 4-(4-methylenepiperidin-1-yl)benzoate

A 0° C. solution of methyltriphenylphosphonium bromide (500 mg, 1.4mmol) in THF (1.5 mL) was treated dropwise with 1M sodiumhexamethyldisilazide in THF (1.4 mL), stirred for 15 minutes, and addeddropwise to a 0° C. solution of Example 158B (0.25 g, 1.0 mmol) in THF(2.1 mL). After stirring for 15 minutes, the reaction was quenched withwater and was extracted with ethyl acetate. The combined extracts werewashed with brine, dried (MgSO₄), filtered, and concentrated. Theconcentrate was purified by flash column chromatography on silica gelwith 9:1 hexanes/ethyl acetate to provide the desired product. MS (DCI)m/e 246 (M+H)⁺.

EXAMPLE 158D ethyl 4-(6-azaspiro(2.5)oct-6-yl)benzoate

A mixture of methyl-3-nitro-1-nitrosoguanidine (1.18 g, 8.1 mmol), 40%KOH (3.4 mL), and diethyl ether (12 mL) at 0° C. was stirred for 10minutes. The organic phase was added slowly to a −25° C. solution ofExample 158C and Pd(OAc)₂ (18 Mg, 0.11 mmol) in THF (8.8 mL). Themixture was stirred for 1 hour at −20° C. and concentrated. Theconcentrate was purified by flash column chromatography on silica gelwith 9:1 hexanes/ethyl acetate to provide the desired product. MS (DCI)m/e 260 (M+H)⁺.

EXAMPLE 158E 4-(6-azaspiro(2.5)oct-6-yl)benzoic acid

The desired product was prepared by substituting Example 158D forExample 119B in Example 119C. MS (DCI) m/e 232 (M+H)⁺.

EXAMPLE 158Ftert-butyl(5R)-5-((4-(((4-(6-azaspiro(2.5)oct-6-yl)benzoyl)amino)sulfonyl)-2-nitrophenyl)amino)-6-(phenylthio)hexylcarbamate

The desired product was prepared by substituting Example 158E andExample 124C for Example 1B and Example 1C, respectively, in Example 1D.MS (ESI(−)) m/e 736 (M−H)⁻.

EXAMPLE 158G4-(((1R)-5-amino-1-((phenylthio)methyl)pentyl)amino)-N-(4-(6-azaspiro(2.5)oct-6-yl)benzoyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 158F forExample 120D in Example 120E. MS (ESI(+)) m/e 654 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ12.0 (s, 1H), 8.54 (d, 1H), 8.32 (d, 1H), 7.86 (dd, 1H),7.75 (d, 2H), 7.25-7.05 (m, 6H), 6.96 (d, 2H), 6.82 (d, 2H), 4.10 (m,1H), 3.50 (m, 4H), 3.90 (m, 6H), 3.43 (m, 4H), 3.36 (m, 2H), 2.72 (m,2H), 1.78 (m, 2H), 1.52 (m, 2H), 1.39 (m, 4H).

EXAMPLE 1594-(((1R)-5-(dimethylamino)-1-((phenylthio)methyl)pentyl)amino)-N-(4-(4,4-dimethylpiperidin-1-yl)benzoyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 124E andExample 119C for Example 1C and Example 1B, respectively, in Example 1D.MS(ESI(+)) m/e 694 (M+H)⁺, ¹H NMR (500 MHz, DMSO-d₆) δ12.06 (s, 1H),10.57 (s, 1H), 8.55 (d, 1H), 8.31 (d, 1H), 7.88 (dd, 1H), 7.78 (d, 2H),7.24 (m, 3H), 7.30 (m, 2H), 7.15 (t, 2H), 7.10 (d, 1H), 7.05 (m, 2H),4.13 (m, 1H), 3.35 (d, 6H), 2.94 (m, 2H), 2.67 (d, 6H), 1.77 (m, 2H),1.65 (m, 2H), 1.59 (m, 4H), 1.51 (m, 4H), 1.43 (m, 4H), 1.38 (m, 2H).

EXAMPLE 160(3R)-3-((4-((((2′-methoxy-4′-(3-((2-methoxyethyl)(methyl)amino)-3-oxopropyl)-1,1′-biphenyl-4-yl)carbonyl)amino)sulfonyl)-2-nitrophenyl)amino)-N,N-dimethyl-4-(phenylthio)butanamide

The desired product was prepared by substitutingN-(2-methoxyethyl)methylamine for neopentylamine in Example 126. MS(ESI(−)) m/e 790 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ12.45 (br s, 1H),8.89 (br d, 1H), 8.57 (d, 1H), 7.90 (d, 2H), 7.85 (dd, 1H), 7.58 (d,2H), 7.30-7.12 (m, 7H), 7.00 (d, 1H), 6.89 (dd, 1H), 4.45 (m, 1H), 3.75(s, 3H), 3.45 (t, 4H), 3.25 (s, 3H), 2.90 (s, 3H), 2.85 (s, 3H), 2.79(s, 3H), 3.10-2.70 (m, 6H), 2.60 (t, 2H).

EXAMPLE 161(3R)-3-((4-(((4′-(3-((3-(dimethylamino)propyl)amino)-3-oxopropyl)-2′-methoxy-1,1′-biphenyl-4-yl)carbonyl)amino)sulfonyl)-2-nitrophenyl)amino)-N,N-dimethyl-4-(phenylthio)butanamide

The desired product was prepared by substitutingN,N-dimethylpropanediamine for neopentylamine in Example 126. MS(ESI(−)) m/e 803 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ9.25 (br s, 1H),8.89 (br d, 1H), 8.57 (d, 1H), 8.05 (br t, 1H), 7.90 (d, 2H), 7.85 (dd,1H), 7.58 (d, 2H), 7.30-7.12 (m, 7H), 7.00 (d, 1H), 6.89 (dd, 1H), 4.45(m, 1H), 3.75 (s, 3H), 3.45 (m 4H), 3.15 (t, 2H), 2.90 (s, 3H), 2.80 (s,3H), 2.75 (2s, 6H), 3.10-2.70 (m, 4H), 2.45(m, 2H), 1.75 (m, 2H).

EXAMPLE 1624-(((4-(aminomethyl)bicyclo(2.2.2)oct-1-yl)methyl)amino)-N-(4-(8-azaspiro(4.5)dec-8-yl)benzoyl)-3-nitrobenzenesulfonamideEXAMPLE 162Atert-butyl(4-(((4-(aminosulfonyl)-2-nitrophenyl)amino)methyl)bicyclo(2.2.2)oct-1-yl)methylcarbamate

A suspension of 1,4-diaminomethyl(2,2,2)bicyclooctane (1.04 g, 6.2mmol), diisopropylethylamine (2 mL) and Example 122C (1.36 g, 6.2 mmol)in 1,2-dichloroethane (20 mL) was stirred for 3 days at 75° C. andconcentrated. The concentrate was redissolved in methanol (30 mL),treated with diisopropylethylamine (2 mL) and BOC₂O (1.636 g), heated to50° C., filtered, and concentrated. The concentrate was purified byflash column chromatography on silica gel with 0-3%methanol/dichloromethane to provide the desired product. MS (ESI(−)) m/e467 (M−H)⁻.

EXAMPLE 162B tert-butyl(4-(((4-(((4-(8-azaspiro(4.5)dec-8-yl)benzoyl)amino)sulfonyl)-2-nitrophenyl)amino)methyl)bicyclo(2.2.2)oct-1-yl)methylcarbamate

The desired product was prepared by substituting Example 162A andExample 257C for Example 1C and Example 1B, respectively, in Example 1D.

EXAMPLE 162C4-(((4-(aminomethyl)bicyclo(2.2.2)oct-1-yl)methyl)amino)-N-(4-(8-azaspiro(4.5)dec-8-yl)benzoyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 162B forExample 120D in Example 120E. MS (ESI(−)) m/e 608 (M−H)⁻; ¹H NMR (300MHz, DMSO-d₆) δ11.97 (br s, 1H), 8.63 (d, 1H), 8.48 (t, 1H), 7.93 (dd,1H), 7.71 (d, 2H), 7.70 (br s, 3H), 7.31 (d, 1H), 6.92 (d, 2H),3.74-3.64 (m, 2H), 3.36-3.31 (m, 4H), 3.23 (d, 2H), 2.56 (q, 2H),1.62-1.57 (m, 4H), 1.52-1.40 (m, 16H).

EXAMPLE 163(3R)-3-((4-((((4′-(3-(bis(2-methoxyethyl)amino)-3-oxopropyl)-2′-methoxy-1,1′-biphenyl-4-yl)carbonyl)amino)sulfonyl)-2-nitrophenyl)amino)-N,N-dimethyl-4-(phenylthio)butanamide

The desired product was prepared by substitutingbis(2-methoxyethyl)amine for neopentylamine in Example 126. MS (ESI(−))m/e 834 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ8.89 (br d, 1H), 8.57 (d,1H), 7.90 (d, 2H), 7.85 (dd, 1H), 7.58 (d, 2H), 7.30-7.12 (m, 7H), 7.00(d, 1H), 6.89 (dd, 1H), 4.45 (m, 1H), 3.75 (s, 3H), 3.45 (m, 10H), 3.25(s, 6H), 2.90 (s, 3H), 2.79 (s, 3H), 3.10-2.70 (m, 6H).

EXAMPLE 164(3R)-3-((4-((((4′-(3-((3-(dimethylamino)propyl)(methyl)amino)-3-oxopropyl)-2′-methoxy-1,1′-biphenyl-4-yl)carbonyl)amino)sulfonyl)-2-nitrophenyl)amino)-N,N-dimethyl-4-(phenylthio)butanamide

The desired product was prepared by substitutingN,N,N′-trimethylpropylenediamine for neopentylamine in Example 126. MS(ESI(−)) m/e 817 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ9.25 (br s, 1H),8.89 (br d, 1H), 8.57 (d, 1H), 7.90 (d, 2H), 7.85 (dd, 1H), 7.58 (d, 2),7.30-7.12 (m, 7H), 7.00 (d, 1H), 6.89 (dd, 1H), 4.45 (m, 1H), 3.75 (s,3H), 3.45 (m 4H), 3.15 (t, 2H), 2.98 (s, 3H), 2.90 (s, 3H), 2.80 (s,3H), 2.75 (2s, 6H), 3.10-2.70 (m, 4H), 2.45 (m, 2H), 1.75 (m, 2H).

EXAMPLE 1654-(3-(2-methoxy-4′-((((3-nitro-4-((2-(phenylthio)ethyl)amino)phenyl)sulfonyl)amino)carbonyl)-1,1′-biphenyl-4-yl)propyl)piperazine-1-carboximidamide

A solution Example 183D (200 mg, 0.29 mmol), 1H-pyrazole-1-carboxamidinehydrochloride (42 mg, 0.29 mmol), and diisoopropylethylamine (0.101 mL,0.58 mmol) in DMF was stirred at 45° C. for 24 hours. The mixture waspurified by reverse-phase HPLC using 50% CH₃CN/water to provide thedesired product. MS (ESI(−)) m/e 730 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆)δ2.12 (m, 2H), 2.70 (m, 2H), 3.10 (m, 2H), 3.30 (dd, 2H), 3.25-3.55 (m,6H), 3.68 (m, 4H), 3.79 (s, 3H), 6.92 (d, 1H), 7.04 (s, 1H), 7.15 (s,2H), 7.19 (dd, 1H), 7.25 (d, 2H), 7.32 (m, 2H), 7.49 (s, 1H), 7.58 (d,1H), 7.92 (dd, 1H), 8.62 (d, 1H), 8.80 (dd, 1H).

EXAMPLE 166N-(4-(1-butyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylthio)methyl)propyl)amino)-3-nitrobenzenesulfonamideEXAMPLE 166A 4-bromo-N-butyl-2-nitroaniline

A solution of butylamine (1.25 g, 17.1 mmol) in DMSO (14 mL) was treatedwith 4-bromo-1-fluoro-2-nitrobenzene (1.50 g, 6.82 mmol), heated to 70°C. for 1 hour, added to 1M HCl (60 mL), and extracted with diethyl ether(3×75 mL). The combined extracts were washed with brine (20 mL), dried(Na₂SO₄), filtered, and concentrated to provide the desired product.

EXAMPLE 166B 4-bromo-N¹-butylbenzene-1,2-diamine

A mixture of Example 166A (1.82 g, 6.66 mmol) and tin(II) chloridedihydrate (3.76 g, 16.6 mmol), and concentrated HCl (22 mL) inisopropanol (30 mL) at room temperature was stirred for 90 minutes,adjusted to pH 6.5-7.5 using NaHCO₃ and 6M NaOH, and filtered. Thefilter cake was washed with water and ethyl acetate, and the filtratewas separated. The aqueous phase was extracted with ethyl acetate (3×50mL) and the combined organic phases were washed with brine (20 mL),dried (Na₂SO₄), filtered, and concentrated. The concentrate was purifiedby flash column chromatography on silica gel with 20-50% ethylacetate/hexanes to provide the desired product.

EXAMPLE 166C 5-bromo-1-butyl-1,3-dihydro-2H-benzimidazol-2-one

A mixture of Example 166B (1.36 g, 5.59 mmol) and triphosgene (582 mg,1.96 mmol) in dioxane was heated to reflux for 16 hours andconcentrated. The concentrate was purified by flash columnchromatography on silica gel with 30% ethyl acetate/hexanes to providethe desired product.

EXAMPLE 166D 4-(1-butyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)benzoicacid

The desired product was prepared by substituting Example 166C for6-bromoindole in Example 4A.

EXAMPLE 166EN-(4-(1-butyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylthio)methyl)propyl)amino)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 166D andExample 122G for Example 1B and Example 1C, respectively, in Example 1D.MS (ESI) m/e 715, 717 (M−H)⁻, (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ0.91(t, 3H), 1.30 (q, 2H), 1.63 (tt, 2H), 2.15 (m, 2H), 2.70 (s, 6H), 3.10(m, 2H), 3.30 (d, 2H), 3.80 (t, 2H), 4.10 (m, 1H), 6.89 (t, 2H), 6.95(s, 1H), 6.98 (d, 1H), 7.15-7.25 (m, 3H), 7.26-7.36 (m, 3H), 7.56 (d,2H), 7.85 (dd, 1H), 7.94 (d, 2H), 8.13 (d, 1H), 8.20 (d, 1H), 8.48 (d,1H), 10.91 (s, 1H).

EXAMPLE 167 isobutyl4-(4-((((4-(((1R)-3-morpholin-4-yl-1-((phenylthio)methyl)propyl)amino)-3-nitrophenyl)sulfonyl)amino)carbonyl)phenyl)piperazine-1-carboxylate

The desired product was prepared by substituting Example 131C andExample 463A for Example 1B and Example 1C, respectively, in Example 1D.MS (ESI)(−)) m/e 753. (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ8.51 (d, 1H),8.37 (d, 1H), 7.81 (dd, 1H), 7.76 (d, 2H), 7.32-7.11 (m, 5H), 7.06 (d,1H), 6.91 (d, 2H), 4.20-4.08 (m, 1H), 3.81 (d, 2H), 3.56-3.46 (m, 8H),3.36 (d, 4H), 3.35-3.26 (m, 4H), 2.57-2.45 (m, 2H), 2.09-1.97 (m, 2H),1.88 (heptet, 1H), 0.90 (d, 6H).

EXAMPLE 1684-(3-(2-methoxy-4′-((((3-nitro-4-((2-(phenylthio)ethyl)amino)phenyl)sulfonyl)amino)carbonyl)-1,1′-biphenyl-4-yl)propyl)piperazine-1-carboxamide

A solution of Example 183D and trimethylsilyl isocyanate in THF at roomtemperature was stirred for 24 hours and concentrated. The concentratewas purified by flash column chromatography on silica gel with 10/10/80methanol/acetonitrile/ethyl acetate to provide the desired product. MS(ESI(−)) m/e 731 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ1.79 (m, 2H), 2.31(br s, 6H), 2.51 (dd, 2H), 3.28 (m, 4H), 3.32 (s, 3H), 3.60 (m, 2H),3.73 (s, 3H), 5.91 (s, 2H), 6.85 (d, 1H), 6.92 (s, 1H), 6.97 (d, 1H),7.18 (d, 1H), 7.20 (d, 1H), 7.31 (dd, 2H), 7.39 (m, 3H), 7.88 (d, 2H),8.50 (s, 1H).

EXAMPLE 169N-(4-(2-azaspiro(4.4)non-2-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 120C andExample 77B for Example 1B and Example 1C, respectively, in Example 1D.MS (ESI(−)) m/e 579 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ11.87 (s, 1H),8.76 (t, 1H), 8.60 (d, 1H), 8.32 (d, 1H), 7.91 (dd, 1H), 7.72 (d, 2H),7.37 (dd, 2H), 7.26 (t, 2H), 7.17 (m, 2H), 6.50 (d, 2H), 3.65 (m, 2H),3.25-3.38 (m, 4H), 3.17 (s, 2H), 1.85 (t, 2H), 1.65 (m, 4H), 1.55 (m,4H).

EXAMPLE 1703-nitro-N-(4-(1-(3-phenylpropyl)-1H-benzimidazol-5-yl)benzoyl)-4-((2-(phenylthio)ethyl)amino)benzenesulfonamideEXAMPLE 170A 4-bromo-N¹-(3-phenylpropyl)benzene-1,2-diamine

The desired product was prepared by substituting 3-phenylpropylamine forbutylamine in Examples 166A and 166B.

EXAMPLE 170B 5-bromo-1-(3-phenylpropyl)-1H-benzimidazole

A solution of Example 170A (560 mg, 1.83 mmol) in trimethyl orthoformate(10 mL) at 95° C. was stirred for 16 hours and concentrated. Theconcentrate was purified by flash column chromatography on silica gelwith 50-100% ethyl acetate/hexanes to provide the desired product.

EXAMPLE 170C 4-(1-(3-phenylpropyl)-1H-benzimidazol-5-yl)benzoic acid

The desired product was prepared by substituting Example 170B for6-bromoindole in Example 4A.

EXAMPLE 170D3-nitro-N-(4-(1-(3-phenylpropyl)-1H-benzimidazol-5-yl)benzoyl)-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 170C andExample 77B for Example 1B and Example 1C, respectively, in Example 1D.¹H NMR (300 MHz, DMSO-d₆) δ2.51 (tt, 2H), 2.61 (tt, 2H), 3.28 (t, 2H),3.61 (dt, 2H), 4.30 (t, 2H), 7.00 (d, 1H), 7.15-7.35 (m, 9H), 7.40 (dt,2H), 7.59 (dd, 1H), 7.69 (dd, 2H), 7.89 (dd, 1H), 7.97 (m, 3H), 8.28 (s,1H), 8.52 (d, 1H), 8.52 (t, 1H).

EXAMPLE 171tert-butyl(5R)-5-((4-(((4-(4-ethyl-4-methylpiperidin-1-yl)benzoyl)amino)sulfonyl)-2-nitrophenyl)amino)-6-(phenylthio)hexylcarbamate

The desired product was prepared by substituting Example 123C andExample 124C for Example 1B and Example 1C, respectively, in Example 1D.MS (ESI(−)) m/e 752 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ11.95 (s, 1H),8.54 (d, 1H), 8.31 (d, 1H), 7.84 (dd, 1H), 7.74 (d, 2H), 7.25-7.08 (m,6H), 6.92 (d, 2H), 6.72 (t, 1H), 4.08 (s, 1H, 3.46 (t, 1H), 3.44 (t,1H), 3.24-3.14 (m, 2H), 2.87 (m, 2H), 1.73 (m, 2H), 1.31 (s, 9H),1.40-1.22 (m, 10H), 0.90 (s, 3H), 0.80 (t, 3H).

EXAMPLE 172(3R)-3-((4-((((2′-methoxy-4′-(3-((3-methoxypropyl)amino)-3-oxopropyl)-1,1′-biphenyl-4-yl)carbonyl)amino)sulfonyl)-2-nitrophenyl)amino)-N,N-dimethyl-4-(phenylthio)butanamide

The desired product was prepared by substituting 3-methoxypropylaminefor neopentylamine in Example 126. MS (ESI(−)) m/e 790 (M−H)⁻; ¹H NMR(300 MHz, DMSO-d₆) δ12.45 (br s, 1H), 8.89 (br d, 1H), 8.57 (d, 1H),7.90 (d, 2H), 7.85 (dd, 1H), 7.82 (br t, 1H), 7.58 (d, 2H), 7.30-7.12(m, 7H), 7.00 (d, 1H), 6.89 (dd, 1H), 4.45 (m, 1H), 3.75 (s, 3H), 3.45(t, 2H), 3.25 (t, 2H), 3.18 (s, 3H), 2.90 (s, 3H), 2.79 (s, 3H),3.10-2.70 (m, 6H), 2.45 (t, 2H), 1.60 (m, 2H).

EXAMPLE 173 tert-butyl1-benzyl-2-(4-(4-((((3-nitro-4-((2-(phenylthio)ethyl)amino)phenyl)sulfonyl)amino)carbonyl)phenyl)piperazin-1-yl)ethylcarbamateEXAMPLE 173A3-nitro-4-((2-(phenylthio)ethyl)amino)-N-(4-piperazin-1-ylbenzoyl)benzenesulfonamide

The desired product was prepared by substituting Example 405 for Example120D in Example 120E. MS (ESI(−)) m/e 540 (M−H)⁻.

EXAMPLE 173B tert-butyl1-benzyl-2-(4-(4-((((3-nitro-4-((2-phenylthio)ethyl)amino)phenyl)sulfonyl)amino)carbonyl)phenyl)piperazin-1-yl)ethylcarbamate

A solution of Example 173A (108 mg, 0.2 mmol) and(1-benzyl-2-oxo-ethyl)-carbamic acid tert-butyl ester (50 mg, 0.2 mmol)in 1:1 methanol/THF (8 mL) at room temperature was treated with 1Msodium cyanoborohydride in THF (0.4 mL, 0.4 mmol), stirred for 18 hours,and concentrated. The concentrate was partitioned between ethyl acetateand saturated sodium bicarbonate, and the organic phase was dried(MgSO₄), filtered, and concentrated. The concentrate was purified byflash column chromatography on silica gel with 0-10%methanol/dichloromethane to provide the desired product. MS (ESI(−)) m/e773 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ8.67 (t, 1H), 8.55 (d, 1H), 7.88(dd, 1H), 7.74 (d, 2H), 7.37 (d, 2H), 7.30-7.08 (m, 9H), 6.90 (d, 2H),6.67 (br d, 1H), 3.88-3.80 (m, 1H), 3.64 (q, 2H), 3.31-3.20 (m, 10H),2.81 (dd, 1H), 2.62-2.50 (m, 3H), 1.30 (s, 9H).

EXAMPLE 174(3R)-3-((4-((((4′-(3-(isobutylamino)-3-oxopropyl)-2′-methoxy-1,1′-biphenyl-4-yl)carbonyl)amino)sulfonyl)-2-nitrophenyl)amino)-N,N-dimethyl-4-(phenylthio)butanamide

The desired product was prepared by substituting isobutylamine forneopentylamine in Example 126. MS (ESI(−)) m/e 774 (M−H)⁻; ¹H NMR (300MHz, DMSO-d₆) δ12.45 (br s, 1H), 8.89 (br d, 1H), 8.57 (d, 1H), 7.90 (d,2H), 7.85 (dd, 1H), 7.80 (br t, 1H), 7.58 (d, 2H), 7.30-7.12 (m, 7H),7.00 (d, 1H), 6.89 (dd, 1H), 4.45 (m, 1H), 3.75 (s, 3H), 3.45 (t, 2H),2.90 (s, 3H), 2.79 (s, 3H), 3.10-2.70 (m, 6H), 2.45 (t, 2H), 1.65 (m,1H), 0.80(d, 6H).

EXAMPLE 175N-((4′-fluoro-1,1′-biphenyl-4-yl)carbonyl)-4-((2-hydroxy-1-((phenylthio)methyl)ethyl)amino)-3-nitrobenzenesulfonamideEXAMPLE 175A methyl N-(tert-butoxycarbonyl)-S-phenylcysteinate

The desired product was prepared by substituting DL-BOC-serine methylester for Example 27A in Example 27B.

EXAMPLE 175B tert-butyl 2-hydroxy-1-((phenylthio)methyl)ethylcarbamate

A solution of Example 175A (1.22 g, 3.91 mmol) in toluene (10 mL) at−78° C. was treated with 1M DIBAL-H in toluene (8.6 mL), warmed to roomtemperature over 4 hours, diluted with ethyl acetate (100 mL), washedsequentially with 0.1N HCl (30 mL), water (15 mL), and brine (50 mL),dried (MgSO₄), filtered, and concentrated. The concentrate was purifiedby flash column chromatography on silica gel with 30% ethylacetate/hexanes to provide the desired product. MS (DCI) m/e 284 (M+H)⁺.

EXAMPLE 175C4-fluoro-N-((4′-fluoro-1,1′-biphenyl-4-yl)carbonyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 122C forExample 1C in Example 1D. MS (ESI(−)) m/e 417 (M−H)⁻.

EXAMPLE 175DN-((4′-fluoro-1,1′-biphenyl-4yl)-carbonyl)-4-((2-hydroxy-1-((phenylthio)methyl)ethyl)amino)-3-nitrobenzenesulfonamide

A mixture of Example 175B (100 mg, 0.35 mmol)) and 4M HCl in 1,4-dioxane(10 mL) was stirred at room temperature for 3 hours and concentrated. Amixture of the concentrate and Example 175C (160 mg, 0.38 mmol) wastreated with DMF (2 mL) and N,N-diisopropylethylamine (0.5 mL), stirredfor 18 hours, diluted with ethyl acetate (60 mL), washed with 1N HCl (20mL) and brine (10 mL), dried (MgSO₄), filtered, and concentrated. Theconcentrate was purified by flash column chromatography on silica gelwith 30-100% ethyl acetate/dichloromethane to provide the desiredproduct. MS (ESI(−)) m/e 580 (M−H)⁻; ¹H NMR (400 MHz, DMSO-d₆) δ8.50 (d,1H), 8.42 (d, 1H), 7.95 (d, 2H), 7.70 (dd, 1H), 7.73 (m, 2H), 7.60 (d,2H), 7.40-7.19 (m, 8H), 3.95 (m, 1H), 3.71 (m, 1H), 3.62 (m, 1H), 3.29(m, 2H).

EXAMPLE 176tert-butyl(5R)-5-((4-(((4-(6-azaspiro(2.5)oct-6-yl)benzoyl)amino)sulfonyl)-2-nitrophenyl)amino)-6-(phenylthio)hexylcarbamate

The desired product was prepared by substituting Example 158E andExample 124C for Example 1B and Example 1C, respectively, in Example 1D.MS (ESI (−)) m/e 736; ¹H NMR (300 MHz, DMSO-d₆) δ11.96 (s, 1H), 8.54 (d,1H), 8.31 (d, 1H), 7.84 (dd, 1H), 7.74 (d, 2H), 7.08-7.25 (m, 6H), 6.95(d, 2H), 6.72 (t, 1H), 4.08 (s, 1H), 3.43 (m, 4H), 3.30 (m, 4H), 2.87(m, 2H), 1.37 (m, 4H), 1.31 (s, 9H), 1.25 (m, 2H), 0.33 (s, 4H).

EXAMPLE 177N-(4-(1-butyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)benzoyl)-4-(((1R)-2-hydroxy-1-((phenylthio)methyl)ethyl)amino)-3-nitrobenzenesulfonamideEXAMPLE 177AN-((4-(((1R)-2-((tert-butyl(dimethyl)silyl)oxy)-1-((phenylsulfanyl)methyl)ethyl)amino)-3-nitrophenyl)sulfonyl)-4-(1-butyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)benzamide

The desired product was prepared by substituting Example 166D andExample 278A for Example 1B and Example 1C, respectively, in Example 1D.

EXAMPLE 177BN-(4-(1-butyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)benzoyl)-4-(((1R)-2-hydroxy-1-((phenylthio)methyl)ethyl)amino)-3-nitrobenzenesulfonamide

A mixture of Example 177A (40 mg, 0.05 mmol) and 1M tetrabutylammoniumfluoride in THF (130 uL, 0.13 mmol) in THF (3 mL) at room temperaturewas stirred for 3 hours, treated with 1M HCl (10 mL), and extracted with5% methanol in ethyl acetate (3×20 mL). The combined extracts werewashed with brine (5 mL), dried (Na₂SO₄), filtered, and concentrated.The concentrate was purified by flash column chromatography on silicagel with 20% methanol/ethyl acetate to provide the desired product. MS(ESI) m/e 674, 676 (M−H)⁻, (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ0.91 (t,3H), 1.30 (q, 2H), 1.59 (tt, 2H), 3.28 (t, 2H), 3.67 (m, 1H), 3.80 (t,2H), 3.92 (m, 2H), 5.21 (t, 1H), 6.83 (d, 1H), 7.21 (m, 3H), 7.29 (td,2H), 7.38 (dd, 2H), 7.55 (d, 2H), 7.80 (dd, 1H), 7.94 (d, 2H), 7.95 (d,1H), 8.41 (d, 1H), 8.49 (d, 1H), 10.90 (s, 1H).

EXAMPLE 178N-(2-(dimethylamino)ethyl)-3-(4′-((((4-(((1R)-3-(dimethylamino)-1-((phenylthio)methyl)propyl)amino)-3-nitrophenyl)sulfonyl)amino)carbonyl)-2-methoxy-1,1′-biphenyl-4-yl)-N-methylpropanamideEXAMPLE 178A methyl4′-(3-((2-(dimethylamino)ethyl)(methyl)amino)-3-oxopropyl)-2′-methoxy-1,1′-biphenyl-4-carboxylate

The desired product was prepared by substitutingN,N,N′-trimethylethylenediamine and Example 122L for Example 1C andExample 1B, respectively, in Example 1D. MS (ESI(+)) m/e 399 (M+H)⁺.

EXAMPLE 178B4′-(3-((2-(dimethylamino)ethyl)(methyl)amino)-3-oxopropyl)-2′-methoxy-1,1′-biphenyl-4-carboxylicacid

The desired product was prepared by substituting Example 178A forExample 1A in Example 1B. MS (ESI(−)) m/e 383 (M−H)⁻.

EXAMPLE 178CN-(2-(dimethylamino)ethyl)-3-(4′-((((4-(((1R)-3-(dimethylamino)-1-((phenylthio)methyl)propyl)amino)-3-nitrophenyl)sulfonyl)amino)carbonyl)-2-methoxy-1,1′-biphenyl-4-yl)-N-methylpropanamide

The desired product was prepared by substituting Example 122G andExample 178B for Example 1C and Example 1B, respectively, in Example 1D.MS (ESI(−)) m/e 789 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ2.32 (s, 2H),2.50 (s, 12H), 2.62-2.89 (m, 10H), 2.96 (s, 3H), 3.05 (m, 1H), 3.18 (d,1H), 3.51 (dd, 1H), 3.73 (s, 3H), 4.08 (m, 1H), 6.89 (m, 2H), 6.98 (d,1H), 7.18 (d, 2H), 7.26 (dd, 2H), 7.31 (dd, 2H), 7.38 (d, 2H), 7.81 (dd,1H), 7.89 (d, 2H), 8.26 (d, 1H), 8.48 (d, 1H).

EXAMPLE 179N-(2-(dimethylamino)ethyl)-3-(4′-((((4-(((1R)-5-(dimethylamino)-1-((phenylthio)methyl)pentyl)amino)-3-nitrophenyl)sulfonyl)amino)carbonyl)-2-methoxy-1,1′-biphenyl-4-yl)-N-methylpropanamide

The desired product was prepared by substituting Example 124E andExample 178B for Example 1C and Example 1B, respectively, in Example 1D.MS (ESI(−)) m/e 817 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ0.99 (t, 2H),1.18 (t, 2H), 1.55 (m, 2H), 1.78 (s, 3H), 1.90 (s, 3H), 2.22 (s, 1H),2.40 (s, 3H), 2.59 (s, 3H), 2.65 (m, 2H), 2.82 (s, 3H), 2.83 (m, 1H),2.96 (s, 1H), 3.03 (m, 4H), 3.27 (m, 1H), 3.33 (m, 1H), 3.49 (dd, 1H),3.73 (s, 3H), 4.04 (m, 1H), 6.89 (m, 2H), 6.98 (d, 1H), 7.18 (d, 2H),7.24 (dd, 2H), 7.31 (dd, 2H), 7.38 (d, 2H), 7.82 (dd, 1H), 7.89 (d, 2H),8.15 (d, 1H), 8.48 (d, 1H).

EXAMPLE 180N˜2˜-(4-(((4-(4,4-dimethylcyclohexyl)benzoyl)amino)sulfonyl)-2-nitrophenyl)-N˜1˜,N˜1˜-bis(4-(N-(4-(((4-(4,4-dimethylcyclohexyl)benzoyl)amino)sulfonyl)-2-nitrophenyl)-S-phenylcysteinyl)morpholin-3-yl)-S-phenylcysteinamideEXAMPLE 180AN-tert-butoxycarbonyl-1-morpholin-4-yl-1-oxo-3-(phenylthio)propan-2-amine

A solution of Example 175A (600 mg, 1.92 mmol) and 2M aqueous lithiumhydroxide (4 mL) in methanol (10 mL) at room temperature was stirred for5 hours and concentrated. The concentrate was treated with morpholine(263 mg, 3 mmol), EDCI (555 mg, 2.88 mmol), DMAP (20 mg) and DMF (20mL), stirred for 16 hours, diluted with ethyl acetate (100 mL), washedsequentially with water (50 mL), and brine (20 mL), dried (MgSO₄),filtered, and concentrated. The concentrate was purified by flash columnchromatography on silica gel with 50% ethyl acetate/hexanes to providethe desired product. MS (ESI(+)) m/e 367 (M+H)⁺.

EXAMPLE 180BN²-(4-(aminosulfonyl)-2-nitrophenyl)-N¹,N¹-bis(4-(N-(4-(aminosulfonyl)-2-nitrophenyl)-S-phenylcysteinyl)morpholin-3-yl)-S-phenylcysteinamide

The desired product was prepared by substituting Example 180A andExample 122C for Example 175B and Example 175C, respectively, in Example175D. MS (ESI(+)) m/e 467 (M+H)⁺.

EXAMPLE 180CN˜2˜-(4-(((4-(4,4-dimethylcyclohexyl)benzoyl)amino)sulfonyl)-2-nitrophenyl)-N˜1˜,N˜1˜-bis(4-(N-(4-(((4-(4,4-dimethylcyclohexyl)benzoyl)amino)sulfonyl)-2-nitrophenyl)-S-phenylcysteinyl)morpholin-3-yl)-S-phenylcysteinamide

The desired product was prepared by substituting Example 77A and Example180B for Example 5C and Example 3A, respectively, in Example 5D. MS(ESI(−)) m/e 679 (M−H)⁻; ¹H NMR (400 MHz, methanol-d₄) δ8.98 (d, 1H),8.63 (d, 1H), 7.92 (m, 3H), 7.27 (m, 2H), 7.20 (d, 2H), 7.09 (m, 3H),6.92 (d, 1H), 5.06 (m, 1H), 3.67-3.50 (m, 4H), 3.42 (t, 2H), 2.43 (m,1H), 2.36 (t, 2H), 2.02 (m, 2H), 1.62 (m, 4H), 1.49 (m, 2H), 1.35 (m,2H), 0.98 (s, 3H), 0.94 (s, 3H).

EXAMPLE 181N-(4-(3-(cyclohexylmethyl)-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

A mixture of Example 251D (80 mg, 0.14 mmol), 60% NaH in mineral oil (12mg, 0.29 mmol), 15-crown-5 (64 mg, 0.29 mmol), andbromomethylcyclohexane (27 mg, 0.15 mmol) in DMF (5 mL) was heated to95° C. and stirred for 16 hours, treated with 1M HCl (20 mL), andextracted with 5% methanol in ethyl acetate (3×20 mL). The combinedextracts were washed with brine (5 mL), dried (Na₂SO₄), filtered, andconcentrated. The concentrate was purified by flash columnchromatography on silica gel with ethyl acetate to provide the desiredproduct. MS (ESI(−)) m/e 685 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆)δ0.98-1.26 (m, 5H), 1.57-1.74 (m, 5H), 1.84 (m, 1H), 3.28 (t, 2H), 3.62(dt, 2H), 3.68 (d, 2H), 7.05 (d, 1H), 7.19 (tt, 1H), 7.29 (t, 2H), 7.39(d, 3H), 7.58 (dd, 1H), 7.68 (d, 2H), 7.72 (d, 1H), 7.90 (dd, 1H), 7.95(d, 2H), 8.54 (d, 1H), 8.59 (t, 1H).

EXAMPLE 182N-(4-(1-benzyl-1H-benzimidazol-5-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamideEXAMPLE 182A N¹-benzyl-4-bromobenzene-1,2-diamine

The desired product was prepared by substituting benzylamine for3-phenylpropylamine in Examples 166A and 166B.

EXAMPLE 182BN-(4-(1-benzyl-1H-benzimidazol-5-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 182A forExample 170A in Examples 170B-170D. MS (ESI) m/e 662, 664 (M−H)⁻,(M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ3.27 (t, 2H), 3.61 (dt, 2H), 5.52 (s,2H), 6.99 (d, 1H), 7.20 (tt, 1H), 7.28-7.36 (m, 7H), 7.40 (dd, 2H),7.52-7.67 (m, 5H), 7.88 (dd, 1H), 7.95 (d, 2H), 8.45 (s, 1H), 8.52 (d,1H), 8.52 (t, 1H).

EXAMPLE 183N-((2′-methoxy-4′-(3-piperazin-1-ylpropyl)-1,1′-biphenyl-4-yl)carbonyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamideEXAMPLE 183A tert-butyl4-(3-(2-methoxy-4′-(methoxycarbonyl)-1,1′-biphenyl-4-yl)propanoyl)piperazine-1-carboxylate

The desired product was prepared by substitutingN-tert-butoxycarbonylpiperazine and Example 122L for Example 1C andExample 1B, respectively, in Example 1D. MS (ESI(+)) m/e 483 (M+H)⁺.

EXAMPLE 183B tert-butyl4-(3-(2-methoxy-4′-(methoxycarbonyl)-1,1′-biphenyl-4-yl)propyl)piperazine-1-carboxylate

The desired product was prepared by substituting Example 183A forExample 122F in Example 122G.

EXAMPLE 183C4′-(3-(4-(tert-butoxycarbonyl)piperazin-1-yl)propyl)-2′-methoxy-1,1′-biphenyl-4-carboxylicacid

The desired product was prepared by substituting Example 183B forExample 1A in Example 1B. MS (ESI(−)) m/e 453 (M−H)⁻.

EXAMPLE 183DN-((2′-methoxy-4′-(3-piperazin-1-ylpropyl)-1,1′-biphenyl-4-yl)carbonyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 77B and Example183C for Example 1B and Example 1C, respectively, in Example 1D. Theproduct was dissolved in TFA (5 mL) and stirred at room temperature for90 minutes, concentrated, dissolved in toluene, and concentrated againto provide the desired product. MS (ESI(+)) m/e 690 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ1.99 (m, 2H), 2.69 (t, 2H), 3.10 (m, 2H), 3.30 (t, 4H),3.49 (m, 6H), 3.68 (m, 2H), 3.77 (s, 3H), 6.91 (d, 1H), 7.01 (s, 1H),7.20 (m, 2H), 7.25 (m, 3H), 7.39 (d, 2H), 7.58 (d, 2H), 7.90 (d, 1H),7.93 (dd, 1H), 8.62 (d, 1H), 8.81 (t, 1H).

EXAMPLE 1844-(((1R)-2-hydroxy-1-((phenylthio)methyl)ethyl)amino)-N-((4′-(3-hydroxypropyl)-2′-methoxy-1,1′-biphenyl-4-yl)carbonyl)-3-nitrobenzenesulfonamide

A solution of Example 133D (300 mg, 0.38 mmol) in THF (4 mL) at roomtemperature was treated with 2M LiBH₄ in THF (470 μL, 2.5 eq), stirredfor 2 hours, quenched with a drop of water, and concentrated. Theconcentrate was purified by flash column chromatography on silica gelwith 100% ethyl acetate to provide the desired product. MS (ESI(−)) m/e650 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ1.75 (m, 2H), 2.65 (t, 2H), 3.32(m, 4H), 3.43 (t, 2H), 3.61 (dd, 1H), 3.72 (dd, 1H), 3.77 (s, 3H), 4.06(m, 1H), 6.68 (d, 1H), 6.96 (s, 1H), 7.11 (m, 2H), 7.22 (m, 2H), 7.31(m, 2H), 7.59 (m, 2H), 7.88 (m, 3H), 8.10 (d, 1H), 8.12 (d, 1H).

EXAMPLE 185 tert-butyl(5R)-5-((4-(((4-(2-azaspiro(4.4)non-2-yl)benzoyl)amino)sulfonyl)-2-nitrophenyl)amino)-6-(phenylthio)hexylcarbamate

The desired product was prepared by substituting Example 120C andExample 124C for Example 1B and Example 1C, respectively, in Example 1D.MS(ESI(−)) m/e 750 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ11.87 (s, 1H),8.53 (d, 1H), 8.30 (d, 1H), 7.84 (dd, 1H), 7.74 (d, 2H), 7.25-7.08 (m,6H), 6.72 (t, 1H), 6.51 (d, 2H), 4.08 (s, 1H), 3.17 (s, 2H), 2.87 (m,2H), 1.85 (t, 2H), 1.73 (m, 2H), 1.63 (m, 4H), 1.55 (m, 4H), 1.32 (s,9H), 1.35-1.22 (m, 8H).

EXAMPLE 186N-((4′-(4-(4-methylphenyl)-1,3-oxazol-2-yl)-1,1′-biphenyl-4-yl)carbonyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamideEXAMPLE 186A 4-(ethoxycarbonyl)phenylboronic acid

A suspension of 4-(dihydroxyboryl)benzoic acid (5.0 g, 30.13 mmol) inethanol (16.0 mL) was treated with 4N HCl in dioxane (34.0 mL), heatedto reflux, stirred for 1.5 hours, and concentrated. The concentrate waspartitioned between water (150.0 mL) and diethyl ether (100.0 mL) andthe aqueous layer was extracted with diethyl ether (2×100 mL). Thecombined organic extracts were dried (MgSO₄), filtered, and concentratedto provide the desired product. MS (APCI) m/e 194 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ8.07 (m, 2H), 7.81 (m, 2H), 4.41 (q, 2H), 1.41 (t, 3H).

EXAMPLE 186B 2-(4-bromophenyl)-4-(4-methylphenyl)-1,3-oxazole

A mixture of 2-bromo-4′-methylacetophenone (152 mg, 0.7 mmol) and4-bromobenzamide (200 mg, 1.0 mmol) was heated to 160° C. for 3 hours,cooled to room temperature, dissolved in ethyl acetate (20 mL), andtreated with 5% sodium bicarbonate (20 mL). The layers were separatedand the aqueous layer was extracted with ethyl acetate (2×10 mL). Thecombined extracts were dried (MgSO₄), filtered, and concentrated. Theconcentrate was purified by flash column chromatography on silica gelwith 50% ethyl acetate/hexanes to provide the desired product. MS (DCI)m/e 314, 316 (M−H)⁻, (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ8.70 (s, 1H),8.00-7.97 (m, 2H), 7.79-7.76 (m, 2H), 7.77-7.74 (m, 2H), 7.29-7.27 (m,2H), 2.34 (s, 3H).

EXAMPLE 186C ethyl4′-(4-(4-methylphenyl)-1,3-oxazol-2-yl)-1,1′-biphenyl-4-carboxylate

A solution of Example 186B (140 mg, 0.45 mmol) in ethylene glycoldimethyl ether (7.0 mL) at room temperature was treated withtetrakis(triphenylphosphine)palladium (26 mg, 0.02 mmol), stirred for 5minutes, treated with a solution of Example 186A (104 mg, 0.54 mmol) inethanol (1.5 mL), stirred for 5 minutes, treated with 2M sodiumcarbonate (1.1 mL, 2.23 mmol), heated to reflux, and stirred for 4hours. The reaction mixture was cooled to room temperature andconcentrated. The concentrate was dissolved in water (20 mL) andextracted with diethyl ether (4×20 mL). The combined extracts were dried(MgSO₄), filtered, and concentrated. The concentrate was purified byflash column chromatography on silica gel with 50% ethyl acetate/hexanesto provide the desired product. MS (DCI) m/e 384 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ8.71 (s, 1H), 8.18-8.16 (m, 2H), 8.09-8.06 (m, 4H),7.97-7.89 (m, 4H), 7.30-7.28 (m, 2H), 4.35 (q, 2H), 2.34 (s, 3H), 1.35(t, 3H).

EXAMPLE 186D4′-(4-(4-methylphenyl)-1,3-oxazol-2-yl)-1,1′-biphenyl-4-carboxylic acid

A solution of Example 186C (130 mg, 0.34 mmol) in THF (15.0 mL) andmethanol (5.0 mL) at room temperature was treated with 2N sodiumhydroxide (3.0 mL), stirred for 18 hours, concentrated, treated withwater (2.0 mL), and adjusted to pH<7 with 2N HCl. The precipitate wasfiltered and dried under vacuum to provide the desired product. MS (DCI)m/e 356 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ8.72 (s, 1H), 8.18-8.15 (m,2H), 8.08-8.04 (m, 4H), 7.97-7.86 (m, 4H), 7.31-7.28 (m, 2H), 2.35 (s,3H).

EXAMPLE 186EN-((4′-(4-(4-methylphenyl)-1,3-oxazol-2-yl)-1,1′-biphenyl-4-yl)carbonyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 186D andExample 77B for Example 1B and Example 1C, respectively, in Example 1D.MS (DCI) m/e 691 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ12.51 (br s, 1H),8.79 (t, 1H), 8.69 (s, 1H), 8.65 (d, 1H), 8.16-8.15 (m, 2H), 8.02-8.00(m, 2H), 7.96-7.94 (m, 2H), 7.91-7.89 (m, 2H), 7.79-7.77 (m, 2H),7.38-7.37 (m, 2H), 7.29-7.16 (m, 6H), 3.68 (q, 2H), 3.31 (q, 2H), 2.35(s, 3H).

EXAMPLE 1874-(((1R)-2-(dimethylamino)-1-((phenylthio)methyl)ethyl)amino)-N-((2′-methoxy-4′-(3-morpholin-4-ylpropyl)-1,1′-biphenyl-4-yl)carbonyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 134D andExample 122O for Example 1C and Example 1B, respectively, in Example 1D.MS (ESI(−)) m/e 746 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ1.78 (m, 1H),2.31 (dd, 1H), 2.35 (m, 2H), 2.58 (d, 1H), 2.62 (dd, 1H), 3.00 (s, 6H),3.48 (m, 1H), 3.58 (m, 4H), 3.74 (s, 3H), 4.11 (m, 1H), 6.84 (d, 1H),6.92 (d, 1H), 6.95 (s, 1H), 7.18 (dd, 1H), 7.20 (dd, 2H), 7.30(s, 1H),7.33 (d, 1H), 7.39 (d, 2H), 7.82 (dd, 1H), 7.90 (d, 2H), 8.26 (d, 1H),8.48 (d, 1H).

EXAMPLE 188(3R)-3-((4-((((4′-(3-(cyclopentylamino)-3-oxopropyl)-2′-methoxy-1,1′-biphenyl-4-yl)carbonyl)amino)sulfonyl)-2-nitrophenyl)amino)-N,N-dimethyl-4-(phenylthio)butanamide

The desired product was prepared by substituting cyclobutylamine forneopentylamine in Example 126. MS (ESI(−)) m/e 786 (M−H)⁻; ¹H NMR (300MHz, DMSO-d₆) δ8.89 (br d, 1H), 8.57 (d, 1H), 7.90 (d, 2H), 7.85 (dd,1H), 7.78 (br d, 1H), 7.58 (d, 2H), 7.30-7.12 (m, 7H), 7.00 (d, 1H),6.89 (dd, 1H), 4.45 (m, 1H), 4.00 (m, 1H), 3.75 (s, 3H), 3.45 (t, 2H),2.90 (s, 3H), 2.79 (s, 3H), 3.10-2.70 (m, 4H), 2.45 (t, 2H), 1.78 (m,2H), 1.60 (m, 2H), 1.50 (m, 2H), 1.35 (m, 2H).

EXAMPLE 189 methylN-(4-((((2′-methoxy-4′-(3-morpholin-4-yl-3-oxopropyl)-1,1′-biphenyl-4-yl)carbonyl)amino)sulfonyl)-2-nitrophenyl)-S-phenyl-L-cysteinateEXAMPLE 189A2′-methoxy-4′-(3-morpholin-4-yl-3-oxopropyl)-1,1′-biphenyl-4-carboxylicacid

The desired product was prepared by substituting Example 122M forExample 1A in Example 1B.

EXAMPLE 189B methylN-(4-((((2′-methoxy-4′-(3-morpholin-4-yl-3-oxopropyl)-1,1′-biphenyl-4-yl)carbonyl)amino)sulfonyl)-2-nitrophenyl)-S-phenyl-L-cysteinate

The desired product was prepared by substituting Example 189A andExample 133C for Example 1B and Example 1C, respectively, in Example 1D.MS (ESI(−)) m/e 761 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ2.68 (t, 2H),2.85 (t, 2H), 3.43 (m, 4H), 3.51 (m, 4H), 3.61 (s, 3H), 3.62 (dd, 1H),3.72 (dd, 1H), 3.75 (s, 1H), 3.78 (dd, 1H), 6.91 (d, 1H), 7.02 (s, 1H),7.11 (m, 2H), 7.21 (dd, 2H), 7.32 (m, 2H), 7.52 (d, 2H), 7.89 (d, 2H),7.93 (dd, 1H), 8.54 (d, 1H), 8.82 (d, 1H).

EXAMPLE 190(3R)-3-((4-((((2′-methoxy-4′-(3-((2-methoxyethyl)amino)-3-oxopropyl)-1,1′-biphenyl-4-yl)carbonyl)amino)sulfonyl)-2-nitrophenyl)amino)-N,N-dimethyl-4-(phenylthio)butanamide

The desired product was prepared by substituting 2-methoxyethylamine forneopentylamine in Example 126. MS (ESI(−)) m/e 776 (M−H)⁻; ¹H NMR (300MHz, DMSO-d₆) δ12.45 (br s, 1H), 8.89 (br d, 1H), 8.57 (d, 1H), 7.95 (brt, 1H), 7.90 (d, 2H), 7.85 (dd, 1H), 7.58 (d, 2H), 7.30-7.12 (m, 7H),7.00 (d, 1H), 6.89 (dd, 1H), 4.45 (m, 1H), 3.75 (s, 3H), 3.45 (t, 2H),3.35 (t, 2H), 3.25 (s, 3H), 3.25 (t, 2H), 2.90 (s, 3H), 2.79 (s, 3H),3.10-2.70 (m, 6H), 2.45 (t, 2H).

EXAMPLE 191N-((4′-(2-((2-(dimethylamino)ethyl)(methyl)amino)ethyl)-2′-methoxy-1,1′-biphenyl-4-yl)carbonyl)-4-(((1R)-2-(4-methylpiperazin-1-yl)-1-((phenylthio)methyl)ethyl)amino)-3-nitrobenzenesulfonamideEXAMPLE 191A methyl2′-methoxy-4′-(2-oxoethyl)-1,1′-biphenyl-4-carboxylate

A solution of methoxymethyltriphenylphosphonium chloride (5.8 g, 16.9mmol) in THF (80 mL) at room temperature was treated with 1M LiHMDS inTHF (16.9 mL, 16.9 mmol), stirred for 10 minutes, treated with Example122I, (4.14 g, 15.3 mmol), stirred for 30 minutes, poured into brine,and extracted with ether three times. The combined extracts were washedwith brine, dried (Na₂SO₄), filtered, and concentrated. The concentratewas purified by flash column chromatography on silica gel with 15% ethylacetate/hexanes to provide the desired product. MS (ESI(−)) m/e 283(M−H)⁻.

EXAMPLE 191B methyl4′-(2-((2-(dimethylamino)ethyl)(methyl)amino)ethyl)-2′-methoxy-1,1′-biphenyl-4-carboxylate

The desired product was prepared by substitutingN,N,N′-trimethylethylenediamine and Example 191A for dimethylamine andExample 134A, respectively, in Example 134B. MS (ESI(+)) m/e 371 (M+H)⁺.

EXAMPLE 191C4′-(2-((2-(dimethylamino)ethyl)(methyl)amino)ethyl)-2′-methoxy-1,1′-biphenyl-4-carboxylicacid

The desired product was prepared by substituting Example 191B forExample 1A in Example 1B. MS (ESI(+)) m/e 357 (M+H)⁺.

EXAMPLE 191DN-((4′-(2-((2-(dimethylamino)ethyl)(methyl)amino)ethyl)-2′-methoxy-1,1′-biphenyl-4-yl)carbonyl)-4-(((1R)-2-(4-methylpiperazin-1-yl)-1-((phenylthio)methyl)ethyl)amino)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 148C andExample 191C for Example 1C and Example 1B, respectively, in Example 1D.MS (ESI(−)) m/e 788 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ2.21 (s, 3H),2.38 (s, 3H), 2.44 (s, 3H), 2.57 (s, 3H), 2.62 (m, 4H), 2.79 (m, 2H),3.00 (m, 2H), 3.23 (t, 2H), 3.44 (m, 10H), 3.59 (dd, 1H), 3.75 (s, 3H),3.77 (dd, 1H), 4.11 (m, 1H), 6.92 (d, 1H), 6.96 (d, 1H), 7.05 (s, 1H),7.15 (dd, 1H), 7.24 (dd, 2H), 7.34 (m, 2H), 7.40 (d, 2H), 7.82 (dd, 1H),7.90 (dd, 2H), 8.31 (d, 1H), 8.48 (d, 1H).

EXAMPLE 192(3R)-3-((4-((((4′-(3-((cyclopropylmethyl)amino)-3-oxopropyl)-2′-methoxy-1,1′-biphenyl-4-yl)carbonyl)amino)sulfonyl)-2-nitrophenyl)amino)-N,N-dimethyl-4-(phenylthio)butanamide

The desired product was prepared by substituting aminomethylcyclopropanefor neopentylamine in Example 126. MS (ESI(−)) m/e 758 (M−H)⁻; ¹H NMR(300 MHz, DMSO-d₆) δ8.89 (br d, 1H), 8.57 (d, 1H), 7.99 (br t, 1H), 7.90(d, 2H), 7.85 (dd, 1H), 7.58 (d, 2H), 7.30-7.12 (m, 7H), 7.00 (d, 1H),6.89 (dd, 1H), 4.45 (m, 1H), 3.45 (t, 2H), 2.90 (s, 3H), 2.79 (s, 3H),3.10-2.70 (m, 6H), 2.45 (t, 2H), 0.90 (m, 1H), 0.38 (m, 2H), 0.20 (m,2H).

EXAMPLE 193(3R)-3-((4-((((4′-(3-(cyclopropylamino)-3-oxopropyl)-2′-methoxy-1,1′-biphenyl-4-yl)carbonyl)amino)sulfonyl)-2-nitrophenyl)amino)-N,N-dimethyl-4-(phenylthio)butanamide

The desired product was prepared by substituting cyclopropylamine forneopentylamine in Example 126. MS (ESI(−)) m/e 758 (M−H)⁻; ¹H NMR (300MHz, DMSO-d₆) δ12.45 (br s, 1H), 8.89 (br d, 1H), 8.57 (d, 1H), 7.90 (brt, 1H), 7.90 (d, 2H), 7.85 (dd, 1H), 7.58 (d, 2H), 7.30-7.12 (m, 7H),7.00 (d, 1H), 6.89 (dd, 1H), 4.45 (m, 1H), 2.90 (s, 3H), 2.79 (s, 3H),3.10-2.70 (m, 6H), 2.60 (M, 1h), 2.45 (t, 2H), 0.60 (m, 2H), 0.38 (m2H).

EXAMPLE 1944-(((1R)-5-amino-1-((phenylthio)methyl)pentyl)amino)-N-((2′-methoxy-4′-(3-morpholin-4-ylpropyl)-1,1′-biphenyl-4-yl)carbonyl)-3-nitrobenzenesulfonamide

A mixture of Example 122N (150 mg, 0.39 mmol ) and LiOH (25 mg, 0.58mmol) in THF (3 mL), methanol (1 mL), and water (0.5 mL) was heated to50° C. for 3 hours and concentrated. The concentrate was treated with amixture of Example 124C (205 mg, 0.39 mmol), EDCI (150 mg, 0.78 mmol),and DMAP (240 mg, 1.96 mmol) in DMF (1.5 mL) and 1,2-dichloroethane (1.5mL), stirred at room temperature for 16 hours, diluted with ethylacetate, washed with water and brine, dried (MgSO₄), filtered, andconcentrated. The concentrate was purified by flash columnchromatography on silica gel with 5% methanol/dichloromethane. Theproduct was treated with 1:1 TFA:dichloromethane (2 mL), stirred for 30minutes, and concentrated to provide the desired product. MS (ESI(−))m/e 760 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ10.05 (br s, 1H), 8.55 (d,1H), 8.35 (br d, 1H), 7.90 (d, 2H), 7.85 (dd, 1H), 7.70 (br s, 2H), 7.58(d, 2H), 7.30-7.12 (m, 7H), 7.00 (d, 1H), 6.89 (dd, 1H), 4.10 (m, 1H),3.75 (s, 3H), 3.45-3.35 (m, 8H), 3.15 (m, 4H), 2.75 (m, 2H), 2.70 (t,2H), 2.00 (m, 2H), 1.75 (m, 2H), 1.50 (m, 2H), 1.40 (m, 2H).

EXAMPLE 1954-((2,2-difluoro-2-(phenylthio)ethyl)amino)-N-((4′-fluoro-1,1′-biphenyl-4-yl)carbonyl)-3-nitrobenzenesulfonamideEXAMPLE 195A 2,2-difluoro-2-(phenylthio)ethanamine

A mixture of 2,2-difluoro-2-phenylsulfanylacetamide (1 g, 4.92 mmol) inTHF at room temperature was treated with BH₃.THF (1M, 25 mL), stirredfor 18 hours, quenched with methanol (5 mL), and concentrated. Theconcentrate was treated with 2M HCl and heated to 80° C. for 30 minutesand concentrated. The concentrate was partitioned betweendichloromethane and saturated sodium bicarbonate, and the organic phasewas dried (MgSO₄), filtered, and concentrated to provide the desiredproduct. MS (ESI(+)) m/e 190 (M+H)⁺.

EXAMPLE 195B4-((2,2-difluoro-2-(phenylthio)ethyl)amino)-3-nitrobenzenesulfonamide

A suspension of Example 195A (0.26 g, 1.37 mmol), diisopropylethylamine(0.5 mL), and Example 122C (0.3 g, 1.37 mmol) in 1,2-dichloroethane (10mL) at room temperature was stirred for 16 hours at 75° C., diluted withdichloromethane, washed with water, dried (MgSO₄), filtered, andconcentrated. The concentrate was purified by flash columnchromatography on silica gel with 0-5% methanol/dichloromethane toprovide the desired product. MS (ESI(−)) m/e 388 (M−H)⁻.

EXAMPLE 195C4-((2,2-difluoro-2-(phenylthio)ethyl)amino)-N-((4′-fluoro-1,1′-biphenyl-4-yl)carbonyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 195B forExample 1C in Example 1D. MS (ESI(−)) m/e 586 (M−H)⁻; ¹H NMR (300 MHz,DMSO-d₆) δ8.73 (t, 1H), 8.64 (d, 1H), 7.99 (dd, 1H), 7.95 (d, 2H),7.71-7.80 (m, 4H), 7.59-7.64 (m, 2H), 7.54-7.43 (m, 3H), 7.36-7.27 (m,3H), 4.37-4.24 (m, 2H).

EXAMPLE 196N-(4-(1-butyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 166D andExample 77B for Example 1B and Example 1C, respectively, in Example 1D.MS (ESI(−)) m/e 644 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ0.90 (t, 3H),1.30 (qt, 2H), 1.65 (tt, 2H), 3.28 (t, 2H), 3.61 (dt, 2H), 3.82 (t, 2H),7.02 (d, 1H), 7.16-7.25 (m, 3H), 7.31 (d, 2H), 7.35 (dd, 1H), 7.40 (d,2H), 7.58 (d, 2H), 7.90 (dd, 1H), 7.95 (d, 2H), 8.50 (t, 1H), 8.52 (d,1H), 10.90 (s, 1H).

EXAMPLE 197N-(4-(8-azaspiro(4.5)dec-8-yl)benzoyl)-4-((2,2-difluoro-2-(phenylthio)ethyl)amino)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 257C andExample 195B for Example 1B and Example 1C, respectively, in Example 1D.MS (ESI(−)) m/e 629 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ8.77 (t, 1H),8.64 (d, 1H), 7.99 (dd, 1H), 7.71 (d, 2H), 7.61 (d, 2H), 7.42-7.52 (m,3H), 7.36 (d, 1H), 6.91 (d, 2H), 4.27-4.37 (m, 2H), 1.56-1.63 (m, 4H),1.38-1.48 (m, 6H).

EXAMPLE 1983-nitro-N-(4-(1-octyl-1H-pyrazol-4-yl)benzoyl)-4-((2-(phenylthio)ethyl)amino)benzenesulfonamideEXAMPLE 198A 4-iodo-1-octyl-1H-pyrazole

A solution of 4-iodopyrazole (11.25 g, 6.44 mmol) in DMF (20 mL) at roomtemperature was treated with 60% NaH (271 mg, 6.77 mmol), stirred for 10minutes, treated with 1-bromooctane (1.22 mL, 7.08 mmol), stirred for 30minutes, poured into water, and extracted three times withether/hexanes. The combined extracts were washed with water and brine,dried (MgSO₄), filtered, and concentrated to provide the desiredproduct. MS (ESI(+)) m/e 307 (M+H)⁺.

EXAMPLE 198B 4-(1-octyl-1H-pyrazol-4-yl)benzoic acid

The desired product was prepared by substituting Example 198A for6-bromoindole in Example 4A. MS (ESI(−)) m/e 299 (M−H)⁻.

EXAMPLE 198C3-nitro-N-(4-(1-octyl-1H-pyrazol-4-yl)benzoyl)-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 77B and Example198B for Example 1C and Example 1B, respectively, in Example 1D. MS(ESI(−)) m/e 634 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ0.83 (t, 3H), 1.23(m, 10H), 1.79 (tt, 2H), 3.37 (t, 2H), 3.61 (q, 2H), 4.09 (t, 2H), 7.00(d, 1H), 7.20 (d, 1H), 7.30 (t, 2H), 7.40 (d, 2H), 7.51 (d, 2H), 7.87(t, 2H), 7.89 (dd, 1H), 8.21 (s, 1H), 8.51 (d, 1H), 8.55 (t, 1H).

EXAMPLE 199N-(4-(4-(2-(1,3-dioxan-2-yl)ethylidene)piperidin-1-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamideEXAMPLE 199A ethyl4-(4-(2-(1,3-dioxan-2-yl)ethylidene)piperidin-1-yl)benzoate

The desired product was prepared by substituting(2-(1,3-dioxan-2-yl)ethyl)triphenylphosphonium bromide formethyltriphenylphosphonium bromide in Example 158C. MS (DCI) m/e 346(M+H)⁺.

EXAMPLE 199B 4-(4-(2-(1,3-dioxan-2-yl)ethylidene)piperidin-1-yl)benzoicacid

The desired product was prepared by substituting Example 199A forExample 119B in Example 119C. MS(DCI) m/e 318 (M+H)⁺.

EXAMPLE 199CN-(4-(4-(2-(1,3-dioxan-2-yl)ethylidene)piperidin-1-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 199B andExample 77B for Example 1B and Example 1C, respectively, in Example 1D.MS (ESI(−)) m/e 651; ¹H NMR (300 MHz, DMSO-d₆) δ11.97 (s, 1H), 8.77 (t,1H), 8.60 (d, 1H), 7.91 (dd, 1H), 7.74 (d, 2H), 7.37 (dd, 2H), 7.31-7.14(m, 4H), 6.93 (d, 2H), 5.23 (t, 1H,), 4.48 (t, 1H), 3.97 (dd, 2H),3.72-3.61 (m, 4H), 3.39 (t, 4H), 3.31 (m, 2H), 2.23 (m, 6H), 1.91-1.78(m, 1H), 1.32 (m, 1H).

EXAMPLE 2004-(3-(2-methoxy-4′-((((3-nitro-4-((2-(phenylthio)ethyl)amino)phenyl)sulfonyl)amino)carbonyl)-1,1′-biphenyl-4-yl)propyl)-N,N-dimethylpiperazine-1-carboxamide

A solution of Example 183D (108 mg, 0.157 mmol) and triethylamine (45μL, 0.32 mmol) in THF (2 mL) at room temperature was treated withdimethylcarbamic chloride (14 uL, 0.157 mmol), and stirred for 30minutes. The mixture was purified by flash column chromatography onsilica gel with 10:10:80 methanol/acetonitrile/ethyl acetate to providethe desired product. MS (ESI(−)) m/e 759 (M−H)⁻; ¹H NMR (300 MHz,DMSO-d₆) δ1.93 (m, 2H), 2.65 (t, 2H), 2.74 (s, 6H), 2.89 (m, 2H), 3.08(m, 4H), 3.34 (m, 6H), 3.61 (m, 2H), 3.75 (s, 3H), 6.88 (d, 1H), 6.96(s, 1H), 7.01 (d, 1H), 7.21 (m, 2H), 7.30 (t, 2H), 7.41 (m, 3H), 7.88(d, 1H), 7.89 (d, 2H), 8.51 (d, 1H), 8.54 (t, 1H).

EXAMPLE 201N-(4-(5-(3-(4-methylpiperazin-1-yl)-3-oxopropyl)quinolin-8-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamideEXAMPLE 201A 5-iodoquinolin-8-ol

A solution of 8-hydroxyquinoline (25.00 g, 172 mmol), sodium iodide(27.10 g, 181 mmol), and 6M NaOH (30.14 mL, 181 mmol) in methanol at 0°C. was treated with 5.25% aqueous NaOCl (13.46 g, 181 mmol) dropwiseover 4 hours, stirred for 16 hours, adjusted to pH 7 with 6M HCl and pH7 buffer, and extracted with 5% methanol in ethyl acetate (3×200 mL).The combined extracts were washed with brine (100 mL), dried (Na₂SO₄),filtered, and concentrated. The concentrate was dissolved in 10%methanol/ethyl acetate and filtered. The filtrate was dried (Na₂SO₄),filtered, and concentrated to provide the desired product.

EXAMPLE 201B 8-((tert-butyl(dimethyl)silyl)oxy)-5-iodoquinoline

A mixture of Example 201A (10.40 g, 38.4 mmol), tert-butyldimethylsilylchloride (6.07 g, 40.3 mmol), and imidazole (5.49 g, 80.6 mmol) in DMF(75 mL) at room temperature was stirred for 16 hours, treated with water(300 mL), and extracted with diethyl ether (3×400 mL). The combinedextracts were washed with brine (100 mL), dried (Na₂SO₄), filtered, andconcentrated. The concentrate was purified by flash columnchromatography on silica gel with 10% ethyl acetate/hexanes to providethe desired product.

EXAMPLE 201C tert-butyl(2E)-3-(8-((tert-butyl(dimethyl)silyl)oxy)quinolin-5-yl)prop-2-enoate

A mixture of Example 201B (5.00 g, 13.0 mmol), tert-butylacrylate (2.00g, 15.6 mmol), palladium(II) acetate (175 mg, 0.78 mmol), andtri-o-tolylphosphine (951 mg, 3.12 mmol) in a sealed tube withtriethylamine (8 mL) and acetonitrile (38 mL) was heated to 120° C. for16 hours and then concentrated. The concentrate was purified by flashcolumn chromatography on silica gel with 10-100% ethyl acetate/hexanesto provide the desired product.

EXAMPLE 201D tert-butyl3-(8-((tert-butyl(dimethyl)silyl)oxy)quinolin-5-yl)propanoate

A mixture of Example 201C (4.03 g, 10.5 mmol) and Rh(PPh₃)₃Cl (972 mg,1.05 mmol) in toluene (40 mL) was degassed and flushed with hydrogenthree times. The solution was heated to 60° C. under a hydrogenatmosphere for 16 hours and concentrated. The concentrate was purifiedby flash column chromatography on silica gel with 5-10% ethylacetate/hexanes to provide the desired product.

EXAMPLE 201E tert-butyl 3-(8-hydroxyquinolin-5-yl)propanoate

The desired product was prepared by substituting Example 201D forExample 177A in Example 177B.

EXAMPLE 201F tert-butyl3-(8-(((trifluoromethyl)sulfonyl)oxy)quinolin-5-yl)propanoate

A mixture of Example 201E (1.57 g, 5.74 mmol), N-(2-pyridyl)triflimide(2.16 g, 6.03 mmol), and N,N-diisopropylethylamine (816 mg, 6.31 mmol)in dichloromethane (25 mL) was heated to reflux for 16 hours and thenconcentrated. The concentrate was purified by flash columnchromatography on silica gel with 30% ethyl acetate/hexanes to providethe desired product.

EXAMPLE 201G methyl4-(5-(3-tert-butoxy-3-oxopropyl)quinolin-8-yl)benzoate

The desired product was prepared by substituting Example 201F forExample 5A in Example 5B.

EXAMPLE 201H 3-(8-(4-(methoxycarbonyl)phenyl)quinolin-5-yl)propanoicacid

A mixture of Example 201G (1.26 g, 3.22 mmol) and triethylsilane (1.12g, 9.66 mmol) in TFA (10 mL) was heated to 50° C. for 16 hours andconcentrated. The concentrate was purified by flash columnchromatography on silica gel with 5% methanol/ethyl acetate to providethe desired product.

EXAMPLE 201I methyl 4-(5-(3-chloro-3-oxopropyl)quinolin-8-yl)benzoate

A solution of Example 201H (1.65 g, 4.92 mmol) in dichloromethane (15mL) at room temperature was treated oxalyl chloride (344 mg, 2.71 mmol),stirred for 20 minutes, treated with toluene (25 mL), and concentratedto provide the desired product.

EXAMPLE 201J methyl4-(5-(3-(4-methylpiperazin-1-yl)-3-oxopropyl)quinolin-8-yl)benzoate

A mixture of Example 201I (300 mg, 0.85 mmol), 1-methylpiperazine (111mg, 1.11 mmol), and pyridine (74 mg, 0.94 mmol) in dioxane (4 mL) atroom temperature was stirred for 75 minutes and purified by flash columnchromatography on silica gel with 90:10:0.5dichloromethane/methanol/concentrated ammonium hydroxide to provide thedesired product.

EXAMPLE 201K4-(5-(3-(4-methylpiperazin-1-yl)-3-oxopropyl)quinolin-8-yl)benzoic acid

The desired product was prepared by substituting Example 201J forExample 1A in Example 1B.

EXAMPLE 201LN-(4-(5-(3-(4-methylpiperazin-1-yl)-3-oxopropyl)quinolin-8-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 201K andExample 77B for Example 1B and Example 1C, respectively, in Example 1D.MS (ESI) m/e 737, 739 (M−H)⁻, (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ2.37(s, 3H), 2.53 (m, 4H), 2.78 (t, 2H), 3.17 (t, 2H), 3.27 (t, 2H),3.40-3.57 (m, 4H), 3.61 (dt, 2H), 7.01 (d, 1H), 7.20 (tt, 1H), 7.31 (t,2H), 7.40 (d, 2H), 7.54-7.62 (m, 4H), 7.68 (d, 1H), 7.90 (dd, 1H), 7.96(d, 2H), 8.52 (d, 1H), 8.54 (t, 1H), 8.57 (d, 1H), 8.89 (dd, 1H).

EXAMPLE 202 tert-butyl4-(3-(2-methoxy-4′-((((3-nitro-4-((2-(phenylthio)ethyl)amino)phenyl)sulfonyl)amino)carbonyl)-1,1′-biphenyl-4-yl)propyl)piperazine-1-carboxylate

The desired product was prepared by substituting (BOC)₂O fordimethylcarbamic chloride in Example 200. MS (ESI(−)) m/e 788 (M−H)⁻; ¹HNMR (300 MHz, DMSO-d₆) δ1.93 (m, 2H), 2.65 (t, 2H), 2.74 (s, 6H), 2.89(m, 2H), 3.08 (m, 4H), 3.34 (m, 6H), 3.61 (m, 2H), 3.75 (s, 3H), 6.86(d, 1H), 6.96 (s, 1H), 7.01 (d, 1H), 7.21 (m, 2H), 7.31 (t, 2H), 7.40(m, 4H), 7.89 (d, 2H), 8.51 (d, 1H), 8.54 (t, 1H).

EXAMPLE 203N-(4-(4-(2-(1,3-dioxan-2-yl)ethyl)piperidin-1-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamideEXAMPLE 203A ethyl4-(4-(2-(1,3-dioxan-2-yl)ethyl)piperidin-1-yl)benzoate

A mixture of Example 199A (1.2 g, 3.6 mmol), Pd/C (0.42 g), and ethylacetate (25 mL) was hydrogenated at 4 atmospheres in a Parr shaker atroom temperature for 3 days. The catalyst was removed by filtration,solvent was evaporated, and the crude product was purified by flashcolumn chromatography on silica gel with 30% ethyl acetate/hexanes toprovide the desired product. MS(DCI) m/e 348 (M+H)⁺.

EXAMPLE 203B 4-(4-(2-(1,3-dioxan-2-yl)ethyl)piperidin-1-yl)benzoic acid

The desired product was prepared by substituting Example 203A forExample 119B in Example 119C. MS(DCI) m/e 320 (M+H)⁺.

EXAMPLE 203CN-(4-(4-(2-(1,3-dioxan-2-yl)ethyl)piperidin-1-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 203B andExample 77B for Example 1B and Example 1C, respectivley, in Example 1Dto obtain the desired product. MS (ESI(−)) m/e 653; ¹H NMR (300 MHz,DMSO-d₆) δ11.96 (s, 1H), 8.77 (t, 1H), 8.60 (d, 1H), 7.91 (dd, 1H), 7.72(d, 2H), 7.37 (m, 2H), 7.14-7.31 (m, 4H), 6.91 (d, 2H), 4.47 (t, 1H),3.87-3.99 (m, 4H), 3.62-3.70 (m, 4H), 3.30 (m, 4H), 2.78 (m, 2H),1.75-1.90 (m, 1H), 1.70 (m, 2H), 1.48 (m, 2H), 1.22-1.32 (m, 3H)1.05-1.13 (m, 1H).

EXAMPLE 204N-(2-(dimethylamino)ethyl)-3-(2-methoxy-4′-((((4-(((1R)-2-(4-methylpiperazin-1-yl)-1-((phenylthio)methyl)ethyl)amino)-3-nitrophenyl)sulfonyl)amino)carbonyl)-1,1′-biphenyl-4-yl)-N-methylpropanamide

The desired product was prepared by substituting Example 148C andExample 178B for Example 1C and Example 1B, respectively, in Example 1D.MS (ESI(−)) m/e 830 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ2.42-2.59 (m,2H), 2.68 (s, 6H), 2.71 (s, 3H), 2.89 (m, 2H), 3.02 (m, 2H), 3.14 (s,3H), 3.29 (m, 12H), 3.62 (m, 2H), 3.75 (s, 3H), 4.04 (m, 1H), 6.89 (d,1H), 6.94 (s, 1H), 6.98 (d, 1H), 7.18 (m, 2H), 7.26 (t, 2H), 7.37 (m,3H), 7.84 (d, 1H), 7.89 (d, 2H), 8.46 (d, 1H), 8.54 (t, 1H).

EXAMPLE 205 methyl4-(3-(2-methoxy-4′-((((3-nitro-4-((2-(phenylthio)ethyl)amino)phenyl)sulfonyl)amino)carbonyl)-1,1′-biphenyl-4-yl)propyl)piperazine-1-carboxylate

The desired product was prepared by substituting methyl chloroformatefor dimethylcarbamic chloride in Example 200. MS (ESI(−)) m/e 746(M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ1.79 (m, 2H), 2.35 (m, 4H), 2.61 (t,2H), 3.28 (t, 2H), 3.35 (m, 6H), 3.59 (s, 3H), 3.61 (m, 2H), 3.74 (s,3H), 6.85 (d, 1H), 6.94 (s, 1H), 6.98 (d, 1H), 7.20 (m, 2H), 7.31 (t,2H), 7.40 (m, 3H), 7.88 (d, 1H), 7.89 (d, 2H), 8.51 (d, 1H), 8.52 (t,1H).

EXAMPLE 206N-(4-(8-azaspiro(4.5)dec-8-yl)benzoyl)-4-(((1R)-2-((2-(dimethylamino)ethyl)(methyl)amino)-1-((phenylthio)methyl)ethyl)amino)-3-nitrobenzenesulfonamideEXAMPLE 206A tert-butyl(1R)-2-((2-(dimethylamino)ethyl)(methyl)amino)-1-((phenylthio)methyl)ethylcarbamate

The desired product was prepared by substitutingN,N,N′-trimethylethylenediamine for dimethylamine in Example 134B. MS(ESI(−)) m/e 366 (M−H)⁻.

EXAMPLE 206B(2R)-N¹-(2-(dimethylamino)ethyl)-N¹-methyl-3-(phenylthio)propane-1,2-diamine

The desired product was prepared by substituting Example 206A forExample 133A in Example 133B.

EXAMPLE 206C4-(((1R)-2-((2-(dimethylamino)ethyl)(methyl)amino)-1-((phenylthio)methyl)ethyl)amino)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 122C andExample 206B for Example 1D and 2,2-dimethylcyclopentylamine,respectively, in Example 1E. MS (ESI(−)) m/e 466 (M−H)⁻.

EXAMPLE 206DN-(4-(8-azaspiro(4.5)dec-8-yl)benzoyl)-4-(((1R)-2-((2-(dimethylamino)ethyl)(methyl)amino)-1-((phenylthio)methyl)ethyl)amino)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 257C andExample 206C for Example 1B and Example 1C, respectively, in Example 1D.MS (ESI(−)) m/e 707 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ1.41 (m, 4H),1.48 (m, 4H), 1.59(m, 4H), 2.23 (m, 2H), 2.64 (s, 6H), 2.67 (s, 3H),2.72 (m, 2H), 3.20 (m, 4H), 3.26-3.42 (m, 5H), 6.81 (d, 2H), 6.97 (d,1H), 7.18 (dd, 1H), 7.21 (dd, 2H), 7.31 (d, 2H), 7.72 (d, 2H), 7.82 (dd,1H), 8.20 (d, 1H), 8.43 (s, 1H).

EXAMPLE 207N-(4-(4-(2-amino-3-phenylpropyl)piperazin-1-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 173B forExample 120D in Example 120E. MS (ESI(−)) m/e 673 (M−H)⁻; ¹H NMR (300MHz, DMSO-d₆) δ8.78 (t, 1H), 8.60 (d, 1H), 7.91 (dd, 1H), 7.77 (d, 2H),7.12-7.40 (m, 9H), 6.90-7.04 (m, 2H), 3.60-3.72 (m, 4H), 3.26-3.40 (m,6H), 2.98-3.08 (m, 2H), 2.70-2.84 (m, 4H)

EXAMPLE 2084-(((4-(aminomethyl)bicyclo(2.2.2)oct-1-yl)methyl)amino)-N-((2′-methoxy-4′-(3-morpholin-4-ylpropyl)-1,1′-biphenyl-4-yl)carbonyl)-3-nitrobenzenesulfonamideEXAMPLE 208A tert-butyl(4-(((4-((((2′-methoxy-4′-(3-morpholin-4-ylpropyl)-1,1′-biphenyl-4-yl)carbonyl)amino)sulfonyl)-2-nitrophenyl)amino)methyl)bicyclo(2.2.2)oct-1-yl)methylcarbamate

The desired product was prepared by substituting Example 122O andExample 162A for Example 1B and Example 1C, respectively, in Example 1D.MS (ESI(−)) m/e 804 (M−H)⁻

EXAMPLE 208B4-(((4-(aminomethyl)bicyclo(2.2.2)oct-1-yl)methyl)amino)-N-((2′-methoxy-4′-(3-morpholin-4-ylpropyl)-1,1′-biphenyl-4-yl)carbonyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 208A forExample 120D in Example 120E. MS (ESI(−)) m/e 704 (M−H)⁻; ¹H NMR (300MHz, DMSO-d₆) δ0.3 (br s, 1H), 8.65 (d, 1H), 8.48 (d, 1H), 7.95 (dd,1H), 7.92 (d, 2H), 7.66 (br s, 2H), 7.56 (d 2H), 7.32 (d, 1H), 7.26 (d,1H), 7.02 (d, 1H), 6.93 (dd, 1H), 3.92-4.02 (m, 2H), 3.78 (s, 3H),3.38-3.47 (m, 2H), 3.26-3.37 (m, 4H), 3.10 (br s, 2H), 2.63-2.76 (m,4H), 2.52-2.60 (m, 2H), 2.01-2.08 (m, 2H), 1.42-1.55 (m, 12H).

EXAMPLE 209N-(4-((4-butylbenzyl)oxy)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamideEXAMPLE 209A methyl 4-((4-butylbenzyl)oxy)benzoate

A solution of triphenylphosphine (656 mg, 2.50 mmol) in THF (12 mL) at0° C. was treated with diethyl azodicarboxylate (442 mg, 2.54 mmol),stirred for 20 minutes, treated with ethyl 4-hydroxybenzoate (350 mg,2.30 mmol) and 4-butylbenzyl alcohol (414 mg, 2.52 mmol), warmed to roomtemperature, stirred for 16 hours, and concentrated. The concentrate waspurified by flash column chromatography on silica gel with 30% ethylacetate/hexanes to provide the desired product.

EXAMPLE 209B 4-((4-butylbenzyl)oxy)benzoic acid

The desired product was prepared by substituting Example 209A forExample 1A in Example 1B.

EXAMPLE 209CN-(4-((4-butylbenzyl)oxy)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 209B andExample 77B for Example 1B and Example 1C, respectively, in Example 1D.MS (ESI(−)) m/e 618 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ0.88 (t, 3H),1.29 (tq, 2H), 1.54 (tt, 2H), 2.57 (t, 2H), 3.28 (t, 2H), 3.63 (dt, 2H),5.08 (s, 2H), 6.96 (d, 2H), 7.06 (d, 1H), 7.19 (d, 2H), 7.21 (s, 1H),7.34 (m, 6H), 7.83 (d, 2H), 7.88 (dd, 1H), 8.54 (d, 1H), 8.61 (t, 1H).

EXAMPLE 2104-(3-(2-methoxy-4′-((((3-nitro-4-((2-(phenylthio)ethyl)amino)phenyl)sulfonyl)amino)carbonyl)-1,1′-biphenyl-4-yl)propyl)-N,N-dimethylpiperazine-1-sulfonamide

The desired product was prepared by substituting dimethylsulfamoylchloride for dimethylcarbamic chloride in Example 200. MS (ESI(−)) m/e795 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ1.89 (m, 2H), 2.65 (m, 2H), 2.77(s, 6H), 2.84 (m, 2H), 3.10 (m, 8H), 3.28 (m, 2H), 3.63 (dd, 2H), 3.76(s, 3H), 6.89 (d, 1H), 6.97 (s, 1H), 7.09 (d, 1H), 7.21 (m, 2H), 7.29(t, 2H), 7.39 (m, 2H), 7.47 (d, 2H), 7.88 (d, 1H), 7.90 (dd, 1H), 8.55(d, 1H), 8.64 (t, 1H).

EXAMPLE 2114-(((1R)-2-(2,5-dioxopyrrolidin-1-yl)-1-((phenylthio)methyl)ethyl)amino)-N-((2′-methoxy-4′-(3-morpholin-4-yl-3-oxopropyl)-1,1′-biphenyl-4-yl)carbonyl)-3-nitrobenzenesulfonamide

A solution of succinimide (24 mg, 0.245 mmol), triphenylphosphine (71mg, 0.27 mmol), and DEAD (43 uL, 0.27 mmol) in THF (3 mL) at roomtemperature was treated with Example 281B (90 mg, 0.122 mmol), stirredfor 30 minutes, and purified by flash column chromatography on silicagel with 5% methanol/ethyl acetate to provide the desired product. MS(ESI(−)) m/e 814 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ1.79 (m, 2H), 2.35(m, 4H), 2.61 (t, 2H), 3.28 (t, 2H), 3.35 (m, 6H), 3.59 (s, 3H), 3.61(m, 2H), 3.74 (s, 3H), 6.91 (d, 1H), 7.01 (s, 1H), 7.03 (d, 1H), 7.16(m, 1H), 7.21 (t, 2H), 7.31 (m, 2H), 7.56 (d, 2H), 7.89 (d, 3H), 8.37(d, 1H), 8.54 (t, 1H).

EXAMPLE 212N-(4-(8-azaspiro(4.5)dec-8-yl)benzoyl)-4-((3-(dimethylamino)-2-(phenylthio)propyl)amino)-3-nitrobenzenesulfonamideEXAMPLE 212A 2-cyano-N,N-dimethyl-2-(phenylthio)acetamide

A suspension of 2-bromo-2-cyano-N,N-dimethylacetamide (3.80 g, 20 mmol),potassium carbonate (2.902 g, 21 mmol) and thiophenol (2.314 g, 21 mmol,2.16 mL) in acetonitrile (20 mL) was heated to 50° C. for 3 days. Themixture was diluted with water (100 mL) and extracted with ethyl acetate(2×50 mL). The combined extracts were combined and concentrated. Theconcentrate was purified by column chromatography on silica gel with0-50% ethyl acetate/hexanes to provide the desired product. MS (ESI(+))m/e 221 (M+H)⁺.

EXAMPLE 212B N,N-dimethyl-2-(phenylthio)propane-1,3-diamine

Example 212A (0.76 g, 3.45 mmol) was treated with 1M BH₃.THF (15 mL),stirred at room temperature for 18 hours, quenched with methanol (5 mL),and concentrated. The concentrate was heated with 2M HCl (50 mL)concentrated, treated with 40% KOH (1-2 mL) and extracted withdichloromethane (25 mL×2). The combined extracts were dried (MgSO₄),filtered, and concentrated to provide the desired product. MS (ESI(+))m/e 211 (M+H)⁺.

EXAMPLE 212C4-((3-(dimethylamino)-2-(phenylthio)propyl)amino)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 212B forExample 195A in Example 195B. MS (ESI(−)) m/e 409 (M−H)⁻.

EXAMPLE 212DN-(4-(8-azaspiro(4.5)dec-8-yl)benzoyl)-4-((3-(dimethylamino)-2-(phenylthio)propyl)amino)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 257C andExample 212C for Example 1B and Example 1C, respectively, in Example 1D.MS (ESI(−)) m/e 650 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ8.98 (t, 1H),8.56 (d, 1H), 7.88 (dd, 1H), 7.71 (d, 2H), 7.48-7.44 (m, 2H), 7.35-7.26(m, 3H), 7.02 (d, 1H), 6.87 (d, 2H), 3.82-3.79 (m, 1H), 3.67-3.59 (m,2H), 3.32-3.24 (m, 4H), 2.86-2.67 (m, 2H), 2.39 (br s, 6H), 1.61-1.56(m, 4), 1.51-1.40 (m, 8H).

EXAMPLE 213N-(4-(2-but-3-enyl-1,3-benzothiazol-5-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamideEXAMPLE 213A 5-bromo-2-but-3-enyl-1,3-benzothiazole

A solution of 5-bromo-2-methylbenzothioazole (1.00 g, 4.38 mmol) in THF(25 mL) at −78° C. was treated with 1.5M LDA in cyclohexane (4.40 mL,6.60 mmol), stirred for 45 minutes, treated with allyl bromide (1.33 g,10.99 mmol), stirred for 1 hour, quenched with 1M HCl, warmed to roomtemperature, added to water (50 mL), and extracted with ethyl acetate(3×200 mL). The combined extracts were washed with brine (25 mL), dried(Na₂SO₄), filtered, and concentrated. The concentrate was purified byflash column chromatography on silica gel with 8% ethyl acetate/hexanesto provide the desired product.

EXAMPLE 213B 4-(2-but-3-enyl-1,3-benzothiazol-5-yl)benzoic acid

The desired product was prepared by substituting Example 213A for6-bromoindole in Example 4A.

EXAMPLE 213CN-(4-(2-but-3-enyl-1,3-benzothiazol-5-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 213B andExample 77B for Example 1B and Example 1C, respectively, in Example 1D.MS (ESI) m/e 643, 645 (M−H)⁻, (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ2.59(dt, 2H), 3.24 (t, 2H), 3.26 (t, 2H), 3.61 (dt, 2H), 5.02 (dq, 1H), 5.14(dq, 1H), 5.92 (m, 1H), 7.02 (d, 1H), 7.19 (tt, 1H), 7.30 (t, 2H), 7.39(d, 2H), 7.74 (d, 3H), 7.89 (dd, 1H), 7.97 (d, 2H), 8.10 (d, 1H), 8.22(d, 1H), 8.54 (d, 1H), 8.56 (t, 1H).

EXAMPLE 214N-(4-(1-((1-hydroxycyclohexyl)methyl)-1H-benzimidazol-5-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamideEXAMPLE 214A 1-(((2-amino-4-bromophenyl)amino)methyl)cyclohexanol

The desired product was prepared by substituting1-aminomethyl-1-cyclohexanol hydrochloride for butylamine in Examples166A, adding 2M NaOH (2.5 mL) to the reaction, and then substituting theresulting product for Example 166A in Example 166B.

EXAMPLE 214B 1-((5-bromo-1H-benzimidazol-1-yl)methyl)cyclohexanol

The desired product was prepared by substituting Example 214A forExample 170A in Example 170B.

EXAMPLE 214C

4-(1,3,2-dioxaborinan-2-yl)benzoic acid

A mixture of 4-(dihydroxyboryl)benzoic acid (30.00 g, 181 mmol) and1,3-propanediol (15.20 g, 200 mmol) in toluene (750 mL) at 140° C. wasstirred for 6 hours while collecting the water removed by azeotropeformation. The mixture was concentrated to provide the desired product.

EXAMPLE 214DN-(4-(1,3,2-dioxaborinan-2-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 214C andExample 77B for Example 1B and Example 1C, respectively, in Example 1D.

EXAMPLE 214EN-(4-borylbenzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

A solution of Example 214D (26.26 g, 48.5 mmol) in THF (250 mL) at roomtemperature was treated with 2M KOH (225 mL), stirred for 16 hours, andconcentrated. The concentrate was purified by flash columnchromatography on silica gel with 70-100% ethyl acetate/hexanes toprovide the desired product.

EXAMPLE 214FN-(4-(1-((1-hydroxycyclohexyl)methyl)-1H-benzimidazol-5-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 214B andExample 214E for 6-bromoindole and 4-(dihydroxyboryl)benzoic acid inExample 4A. MS (ESI) m/e 684, 686 (M−H)⁻, (M+H)⁺; ¹H NMR (300 MHz,DMSO-d₆) δ1.17-1.58 (m, 10H), 3.27 (t, 2H), 3.61 (dt, 2H), 4.15 (s, 2H),4.58 (s, 1H), 7.00 (d, 1H), 7.20 (tt, 1H), 7.31 (td, 2H), 7.40 (d, 2H),7.49-7.58 (m, 2H), 7.65 (d, 2H), 7.73 (d, 1H), 7.89 (dd, 1H), 7.96 (d,2H), 8.14 (s, 1H), 8.52 (d, 1H), 8.53 (t, 1H).

EXAMPLE 215 tert-butyl2-((4-(4-((((3-nitro-4-((2-(phenylthio)ethyl)amino)phenyl)sulfonyl)amino)carbonyl)phenyl)piperazin-1-yl)methyl)pyrrolidine-1-carboxylate

The desired product was prepared by substituting2-formylpyrrolidine-1-carboxylic acid tert-butyl ester for(1-benzyl-2-oxo-ethyl)-carbamic acid tert-butyl ester in Example 173B.MS (ESI(−)) m/e 723 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ8.61 (t, 1H),8.53 (d, 1H), 7.88 (dd, 1H), 7.73 (d, 2H), 7.38 (d, 2H), 7.30-7.25 (m,2H), 7.21-7.15 (m, 1H), 7.07 (d, 1H), 6.87 (d, 2H), 3.88-3.78 (m, 1H),3.62 (q, 2H), 3.18-3.30 (m, 10H), 2.72-2.60 (m, 2H), 2.38-2.26 (m, 2H),1.90-1.76 (m, 4H), 1.40 (s, 9H).

EXAMPLE 216N,N-dimethyl-3-(8-(4-((((3-nitro-4-((2-(phenylthio)ethyl)amino)phenyl)sulfonyl)amino)carbonyl)phenyl)quinolin-5-yl)propanamide

The desired product was prepared by substituting dimethylamine for1-methylpiperazine in Example 201. MS (ESI(−)) m/e 682 (M−H)⁻; ¹H NMR(300 MHz, DMSO-d₆) δ2.73 (t, 2H), 2.83 (s, 3H), 2.92 (s, 3H), 3.26 (t,2H), 3.28 (t, 2H), 3.65 (dt, 2H), 7.15 (d, 1H), 7.19 (tt, 1H), 7.29 (td,2H), 7.38 (d, 2H), 7.55-7.62 (m, 2H), 7.66 (d, 2H), 7.69 (d, 1H),7.90-7.98 (m, 3H), 8.57 (d, 1H), 8.60 (t, 1H), 8.70 (m, 1H), 8.88 (dd,1H).

EXAMPLE 217N-((2′-methoxy-4′-((1E)-3-morpholin-4-yl-3-oxoprop-1-enyl)-1,1′-biphenyl-4-yl)carbonyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamideEXAMPLE 217A ethyl2′-methoxy-4′-((1E)-3-morpholin-4-yl-3-oxoprop-1-enyl)-1,1′-biphenyl-4-carboxylate

The desired product was prepared by substituting Example 122L andmorpholine for Example 1B and Example 1C, respectively, in Example 1D.

EXAMPLE 217B2′-methoxy-4′-((1E)-3-morpholin-4-yl-3-oxoprop-1-enyl)-1,1′-biphenyl-4-carboxylicacid

The desired product was prepared by substituting Example 217A forExample 1A in Example 1B. MS (ESI(−)) m/e 366 (M−H)⁻.

EXAMPLE 217CN-((2′-methoxy-4′-((1E)-3-morpholin-4-yl-3-oxoprop-1-enyl)-1,1′-biphenyl-4-yl)carbonyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 217B andExample 77B for Example 1B and Example 1C, respectively, in Example 1D.MS (ESI(−)) m/e 701 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ3.25 (m, 4H),3.47 (m, 2H), 3.61 (m, 4H), 3.68 (s, 3H), 3.72 (dd, 2H), 4.58 (d, 1H),6.92 (m, 3H), 7.20 (t, 1H), 7.31 (m, 3H), 7.40 (m, 4H), 7.58 (dd, 1H),7.90 (m, 3H), 8.48 (m, 2H).

EXAMPLE 218 isobutyl4-(3-(2-methoxy-4′-((((3-nitro-4-((2-(phenylthio)ethyl)amino)phenyl)sulfonyl)amino)carbonyl)-1,1′-biphenyl-4-yl)propyl)piperazine-1-carboxylate

The desired product was prepared by substituting isobutyl chloroformatefor dimethylcarbamic chloride in Example 200. MS (ESI(−)) m/e 788(M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ0.89 (d, 6H), 1.80 (m, 2H), 1.85 (m,1H), 2.39 (m, 4H), 2.62 (t, 2H), 3.28 (t, 2H), 3.40 (m, 4H), 3.59 (m,3H), 3.73 (s, 3H), 3.79 (dd, 1H), 4.02 (m, 1H), 6.86 (d, 1H), 6.94 (s,1H), 6.98 (d, 1H), 7.20 (m, 2H), 7.31 (t, 2H), 7.40 (m, 3H), 7.88 (d,1H), 7.89 (d, 2H), 8.50 (d, 1H), 8.52 (t, 1H).

EXAMPLE 2193-nitro-4-((2-(phenylthio)ethyl)amino)-N-(4-(1,8,8-trimethyl-3-azabicyclo(3.2.1)oct-3-yl)benzoyl)benzenesulfonamideEXAMPLE 219A methyl4-(1,8,8-trimethyl-2,4-dioxo-3-azabicyclo(3.2.1)oct-3-yl)benzoate

The desired product was prepared by substituting methyl 4-aminobenzoateand (+/−)-camphoric anhydride for ethyl 4-aminobenzoate and3,3-dimethylglutaric anhydride, respectively, in Example 119A. MS (DCI)m/e 333 (M+NH₄)⁺.

EXAMPLE 219B methyl4-(1,8,8-trimethyl-3-azabicyclo(3.2.1)oct-3-yl)benzoate

The desired product was prepared by substituting Example 219A forExample 119A in Example 119B. MS (DCI) m/e 288 (M+H)⁺.

EXAMPLE 219C 4-(1,8,8-trimethyl-3-azabicyclo(3.2.1)oct-3-yl)benzoic acid

The desired product was prepared by substituting Example 219B forExample 119B in Example 119C. MS (DCI) m/e 274 (M+H)⁺.

EXAMPLE 219D3-nitro-4-((2-(phenylthio)ethyl)amino)-N-(4-(1,8,8-trimethyl-3-azabicyclo(3.2.1)oct-3-yl)benzoyl)benzenesulfonamide

The desired product was prepared by substituting Example 219C andExample 77B for Example 1B and Example 1C, respectively, in Example 1D.MS (ESI(−)) m/e 607 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ11.96 (s, 1H),8.76 (t, 1H), 8.60 (d, 1H), 7.91 (dd, 1H), 7.74 (d, 2H), 7.37 (d, 2H),7.15-7.29 (m, 4H), 6.80 (d, 2H), 3.67 (m, 2H), 3.43 (d, 1H), 3.29 (m,2H), 3.15 (m, 2H), 2.85 (d, 1H, J=11.5), 1.90 (m, 2H), 1.60 (m, 2H),1.40 (m, 1H), 0.91 (m, 9H).

EXAMPLE 2203-nitro-4-((2-(phenylthio)ethyl)amino)-N-(4-pyrrolidin-1-ylbenzoyl)benzenesulfonamideEXAMPLE 220A methyl 4-(2,5-dioxopyrrolidin-1-yl)benzoate

The desired product was prepared by substituting methyl 4-aminobenzoateand succinic anhydride for ethyl 4-aminobenzoate and3,3-dimethylglutaric anhydride, respectively, in Example 119A. MS (DCI)m/e 251 (M+NH₄)⁺.

EXAMPLE 220B methyl 4-pyrrolidin-1-ylbenzoate

The desired product was prepared by substituting Example 220A forExample 119A in Example 119B MS (DCI) m/e 206 (M+H)⁺.

EXAMPLE 220C 4-pyrrolidin-1-ylbenzoic acid

The desired product was prepared by substituting Example 220B forExample 119B in Example 119C. MS (DCI) m/e 192 (M+H)⁺.

EXAMPLE 220D3-nitro-4-((2-(phenylthio)ethyl)amino)-N-(4-pyrrolidin-1-ylbenzoyl)benzenesulfonamide

The desired product was prepared by substituting Example 220C andExample 77B for Example 1B and Example 1C, respectively, in Example 1D.MS (ESI(−)) m/e 527 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ11.87 (s, 1H),8.77 (t, 1H), 8.60 (d, 1H), 7.91 (dd, 1H), 7.73 (d, 2H), 7.37 (d, 2H),7.15-7.28 (m, 4H), 6.53 (d, 2H), 3.67 (m, 2H), 3.30 (m, 6H), 1.95 (m,4H).

EXAMPLE 221N-(4-(5-(3-morpholin-4-yl-3-oxopropyl)quinolin-8-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting morpholine for1-methylpiperazine in Example 201. MS (ESI) m/e 724, 726 (M−H)⁻, (M+H)⁺;¹H NMR (300 MHz, DMSO-d₆) δ2.76 (t, 2H), 3.27 (t, 2H), 3.29 (t, 2H),3.34-3.53 (m, 8H), 3.60 (dt, 2H), 6.99 (d, 1H), 7.20 (t, 1H), 7.31 (t,2H), 7.40 (d, 2H), 7.50-7.61 (m, 4H), 7.67 (d, 1H), 7.89 (d, 1H), 7.95(d, 2H), 8.50 (t, 1H), 8.51 (d, 1H), 8.56 (d, 1H), 8.89 (d, 1H).

EXAMPLE 222N-((4′-(3-(4-acetylpiperazin-1-yl)propyl)-2′-methoxy-1,1′-biphenyl-4-yl)carbonyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared from acetyl chloride fordimethylcarbamic chloride in Example 200. MS (ESI(−)) m/e 703 (M−H)⁻; ¹HNMR (300 MHz, DMSO-d₆) δ1.91 (m, 2H), 2.01 (s, 3H), 2.67 (m, 4H), 2.72(m, 2H), 3.28 (m, 4H), 3.59 (m, 6H), 3.75 (s, 3H), 4.05 (dd, 1H), 6.88(d, 1H), 6.95 (s, 1H), 7.01 (d, 1H), 7.20 (m, 2H), 7.31 (t, 2H), 7.40(m, 3H), 7.70 (d, 1H), 7.89 (d, 2H), 8.51 (d, 1H), 8.54 (t, 1H).

EXAMPLE 223N-(4-(1-(cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamideEXAMPLE 223A4-(1-(cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)benzoicacid

The desired product was prepared by substituting cyclohexylmethylaminefor n-butylamine in Examples 166A, 166B, 166C, and 166D.

EXAMPLE 223BN-(4-(1-(cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 223A andExample 77B for Example 1B and Example 1C, respectively, in Example 1D.MS (ESI) m/e 684, 686 (M−H)⁻; (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆)δ0.96-1.26 (m, 5H), 1.55-1.72 (m, 5H), 1.80 (m, 1H), 3.27 (t, 2H), 3.63(m, 4H), 6.98 (d, 1H), 7.15-7.25 (m, 3H), 7.30 (t, 3H), 7.40 (d, 2H),7.55 (d, 2H), 7.88 (dd, 1H), 7.93 (d, 2H), 8.51 (d, 1H), 8.51 (t, 1H),10.89 (s, 1H).

EXAMPLE 224 tert-butyl(5R)-5-((4-((((4′-(2-((2-(dimethylamino)ethyl)(methyl)amino)ethyl)-2′-methoxy-1,1′-biphenyl-4-yl)carbonyl)amino)sulfonyl)-2-nitrophenyl)amino)-6-(phenylthio)hexylcarbamate

The desired product was prepared by substituting Example 124C andExample 191C for Example 1C and Example 1B, respectively, in Example 1D.MS (ESI(−)) m/e 861 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ1.32 (s, 9H),2.37 (s, 3H), 2.52 (s, 6H), 2.54 (m, 6H), 2.72 (t, 2H), 2.80 (d, 2H),2.88 (d, 2H), 3.02 (m, 2H), 3.27 (m, 4H), 3.77 (s, 3H), 3.98 (m, 1H),6.70 (m, 1H), 6.89 (d, 1H), 6.90 (s, 1H), 6.99 (d, 1H), 7.18 (m, 1H),7.22 (m, 2H), 7.30 (d, 2H), 7.39 (t, 2H), 7.81 (d, 1H), 7.89 (d, 2H),8.14 (d, 1H), 8.47 (d, 1H)

EXAMPLE 225N-(4-(1-cyclopentyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamideEXAMPLE 225A4-(1-cyclopentyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)benzoic acid

The desired product was prepared by substituting cyclopentylamine forbutylamine in Examples 166A, 166B, 166C, and 166D.

EXAMPLE 225BN-(4-(1-cyclopentyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 225A andExample 77B for Example 1B and Example 1C, respectively, in Example 1D.MS (ESI(−)) m/e 656 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ1.68 (m, 2H),1.91 (m, 4H), 2.05 (m, 2H), 3.28 (t, 2H), 3.62 (dt, 2H), 4.74 (m, 1H),7.03 (d, 1H), 7.15-7.25 (m, 3H), 7.27-7.35 (m, 3H), 7.39 (d, 2H), 7.57(d, 2H), 7.89 (dd, 1H), 7.94 (d, 2H), 8.52 (d, 1H), 8.56 (t, 1H), 10.95(s, 1H),

EXAMPLE 2263-nitro-N-(4-(4-(3-oxopropyl)piperidin-1-yl)benzoyl)-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

A solution of Example 203C (250 mg, 0.4 mmol), in dichloromethane (5mL), TFA (1.5 mL), and 1 drop water was stirred at room temperature for48 hours. The reaction mixture was diluted with dichloromethane, washedsequentially with water, saturated NaHCO₃, and brine, dried (MgSO₄),filtered, and concentrated. The concentrate was purified by flash columnchromatography on silica gel with dichloromethane 0.5-1.0% methanol toprovide the desired product. MS (APCI) m/e 597 (M+H)⁺; ¹H NMR (300 MHz,CDCl₃) δ9.80 (s, 1H), 8.87 (d, 1H), 8.67 (t, 1H), 8.47 (s, 1H), 8.15(dd, 1H), 7.63 (d, 2H), 7.40 (m, 2H), 7.24-7.34 (m, 4H), 6.87 (d, 2H),6.82 (m, 2H), 3.87 (d, 2H), 3.58 (m, 4H), 3.21 (t, 2H), 2.86 (m, 2H),2.50 (m, 2H), 1.80 (m, 2H), 1.62 (m, 2H), 1.55 (s, 4H) 1.31 (m, 2H).

EXAMPLE 227N-(4-(3-butyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting 1-bromobutane forbromomethylcyclohexane in Example 181. MS (ESI) m/e 645, 647 (M−H)⁻,(M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ0.92 (t, 3H), 1.33 (qt, 2H), 1.69(tt, 2H), 3.26 (t, 2H), 3.62 (dt, 2H), 3.85 (t, 2H), 7.05 (d, 1H), 7.19(tt, 1H), 7.29 (t, 2H), 7.39 (d, 3H), 7.58 (dd, 1H), 7.68 (d, 2H), 7.73(d, 1H), 7.89 (dd, 1H), 7.94 (d, 2H), 8.54 (d, 1H), 8.59 (t, 1H).

EXAMPLE 2283-nitro-N-(4-(2-nonyl-1,3-benzothiazol-5-yl)benzoyl)-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting 1-bromooctane for allylbromide in Example 213. MS (ESI) m/e 715, 717 (M−H)⁻, (M+H)⁺; ¹H NMR(300 MHz, DMSO-d₆) δ0.85 (t, 3H), 1.12-1.43 (m, 12H), 1.82 (tt, 2H),3.12 (t, 2H), 3.28 (t, 2H) 3.61 (dt, 2H), 7.02 (d, 1H), 7.19 (t, 1H),7.30 (t, 2H), 7.39 (d, 2H), 7.73 (d, 2H), 7.88 (d, 1H), 7.98 (d, 2H),8.11 (d, 1H), 8.21 (s, 1H), 8.53 (d, 1H), 8.55 (t, 1H).

EXAMPLE 229N-((4′-(3-(4-(2,2-dimethylpropanoyl)piperazin-1-yl)propyl)-2′-methoxy-1,1′-biphenyl-4-yl)carbonyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting pivaloyl chloride fordimethylcarbamic chloride in Example 200. MS (ESI(−)) m/e 772 (M−H)⁻; ¹HNMR (300 MHz, DMSO-d₆) δ1.18 (s, 9H), 1.79 (m, 2H), 2.35 (m, 6H), 2.62(t, 2H), 3.28 (t, 2H), 3.54 (m, 4H), 3.60 (dd, 2H), 3.75 (s, 3H), 6.86(d, 1H), 6.94 (s, 1H), 6.98 (d, 1H), 7.18 (d, 1H), 7.20 (m, 1H), 7.31(t, 2H), 7.40 (t, 4H), 7.88 (d, 1H), 7.89 (d, 2H), 8.49 (d, 1H), 8.51(t, 1H).

EXAMPLE 230N-(4-(3-methoxycyclohept-1-en-1-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamideandN-(4-(6-methoxycyclohept-1-en-1-yl)benzoyl-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamideEXAMPLE 230A 3-methoxycyclohet-1-en-1-yl trifluoroacetate and6-methoxycyclohept-1-en-1-yl trifluoroacetate

The desired product was prepared by substituting 3-methoxycycloheptanonefor 4-tert-butylcyclohexanone in Example 5A.

EXAMPLE 230B methyl 4-(3-methoxycyclohept-1-en-1-yl)benzoate and methyl4-(6-methoxycyclohept-1-en-1-yl)benzoate

The desired product was prepared by substituting Example 230A forExample 5A in Example 5B. MS (DCI (+)) m/e 261 (M+H)⁺.

EXAMPLE 230CN-(4-(3-methoxycyclohept-1-en-1-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamideandN-(4-(6-methoxycyclohept-1-en-1-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

A mixture of Example 230B (70 mg, 0.27 mmol) and LiOH (14 mg, 0.32 mmol)in THF (3 mL), methanol (1.5 mL), and water (0.5 mL) was heated to 50°C. for 3 hour and concentrated. The concentrate was dissolved in DMF(0.5 mL) and treated with a mixture of Example 77B (38 mg, 0.104 mmol),EDCI (50 mg, 0.26 mmol), and DMAP (79 mg, 0.65 mmol) in dichloroethane(0.5 mL). The mixture was stirred for 16 hours, diluted with ethylacetate (50 mL), washed sequentially with 1N HCl (5 mL), water (30 mL)and brine (30 mL), dried (MgSO₄), filtered, and concentrated. Theconcentrate was purified by flash column chromatography on silica gelwith 5% methanol/dichloromethane to provide the desired product. MS(ESI(−)) m/e 580 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ8.78 (br t, 1H),8.60 (d, 1H), 7.92 (dd, 1H), 7.85 (d, 2H), 7.40-7.15 (m, 8H), 6.30 and6.10 (t, 1H), 4.00 and 3.70 (m, 2H), 2.90 and 2.75 (s, 3H), 2.30-1.55(m, 11H).

EXAMPLE 231 tert-butyl(5R)-5-((4-(((4-(1-benzyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)benzoyl)amino)sulfonyl-2-nitrophenyl)amino)-6-(phenylthio)hexylcarbamateEXAMPLE 231A 4-(1-benzyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)benzoicacid

The desired product was prepared by substituting benzylamine forn-butylamine in Examples 166A, 166B, 166C, and 166D.

EXAMPLE 231B tert-butyl(5R)-5-((4-(((4-(1-benzyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)benzoyl)amino)sulfonyl)-2-nitrophenyl)amino)-6-(phenylthio)hexylcarbamate

The desired product was prepared by substituting Example 231A andExample 124C for Example 1B and Example 1C, respectively, in Example 1D.MS (ESI(−)) m/e 849 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ1.32 (m, 11H),1.54 (m, 2H), 1.72 (m, 2H), 2.87 (m, 2.87H), 3.98 (t, 2H), 4.12 (m, 1H),5.02 (d, 2H), 6.72 (t, 2H), 7.01 (d, 1H), 7.07-7.23 (m, 4H), 7.26-7.38(m, 8H), 7.60 (d, 2H), 7.84 (dd, 1H), 7.94 (d, 2H), 8.20 (m, 2H), 8.49(d, 1H), 11.08 (s, 1H).

EXAMPLE 232N-(4-(4-(3-hydroxypropyl)piperidin-1yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

A solution of Example 226 (15 mg, 0.025 mmol) in methanol (0.5 mL) anddichloromethane (2 drops) at 0° C. was treated with NaBH₄ (24 mg, 0.6mmol), stirred for 1 hour, warmed to room temperature, and stirred for90 minutes. The mixture was treated with water and filtered. The filtercake was treated with dichloromethane (5 mL) and methanol (1 drop),stirred for 2 hours, and filtered. The filter cake was washed withdiethyl ether, and dried under vacuum to provide the desired product.MS(ESI(−)) m/e 597 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ8.49 (d, 1H), 8.45(d, 1H), 7.85 (dd, 1H), 7.71 (d, 2H), 7.40 (m, 2H), 7.30 (m, 2H), 7.20(m, 2H), 6.95 (d, 1H), 6.90 (d, 2H), 4.34 (t, 1H), 3.75 (m, 2H), 3.60(m, 2H), 3.39 (m, 2H), 3.25 (m, 2H), 2.65 (m, 2H), 1.71 (m, 2H), 1.45(m, 2H), 1.25-1.11 (m, 4H).

EXAMPLE 233N-(2-(dimethylamino)ethyl)-3-(2-methoxy-4′-((((4-(((1R)-2-morpholin-4-yl-1-((phenylthio)methyl)ethyl)amino)-3-nitrophenyl)sulfonyl)amino)carbonyl)-1,1′-biphenyl-4-yl)-N-methylpropanamide

The desired product was prepared by substituting Example 146C andExample 178B for Example 1C and Example 1B, respectively, in Example 1D.MS (ESI(−)) m/e 817 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ2.18 (dd, 2H),2.21 (s, 6H), 2.32 (dd, 2H), 2.50 (dd, 2H), 2.62 (m, 2H), 2.82 (dd, 2H),2.94 (s, 3H), 2.98 (m, 4H), 3.34 (m, 4H), 3.52 (dd, 2H), 3.74 (s, 3H),4.14 (m, 1H), 0.88 (d, 1H), 6.94 (s, 1H), 6.98 (d, 1H), 7.18 (d, 1H),7.24 (m, 1H), 7.34 (t, 2H), 7.39 (t, 2H), 7.82 (d, 1H), 7.89 (d, 2H),8.32 (d, 1H), 8.46 (d, 1H).

EXAMPLE 234N,N-bis(2-methoxyethyl)-3-(8-(4-((((3-nitro-4-((2-(phenylthio)ethyl)amino)phenyl)sulfonyl)amino)carbonyl)phenyl)quinolin-5-yl)propanamide

The desired product was prepared by substitutingbis(2-methoxyethyl)amine for 1-methylpiperazine in Example 201. MS (ESI)m/e 770, 772 (M−H)⁻, (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ2.79 (t, 2H),3.16 (s, 3H), 3.22 (s, 3H), 3.28 (t, 2H), 3.32 (t, 2H), 3.38 (m, 4H),3.45 (m, 4H), 3.62 (dt, 2H), 7.02 (d, 1H), 7.20 (t, 1H), 7.30 (t, 2H),7.40 (d, 2H), 7.52-7.61 (m, 4H), 7.67 (d, 1H), 7.89 (dd, 1H), 7.95 (d,2H), 8.52-8.58 (m, 3H), 8.88 (dd, 1H).

EXAMPLE 235 tert-butyl2-(4-(4-((((3-nitro-4-((2-(phenylthio)ethyl)amino)phenyl)sulfonyl)amino)carbonyl)phenyl)piperazin-1-yl)ethylcarbamate

The desired product was prepared by substituting (2-oxo-ethyl)-carbamicacid tert-butyl ester for (1-benzyl-2-oxo-ethyl)-carbamic acidtert-butyl ester in Example 173B. MS (ESI(−)) m/e 683 (M−H)⁻; ¹H NMR(300 MHz, DMSO-d₆) δ8.63 (t, 1H), 8.53 (d, 1H), 7.88 (dd, 1H), 7.74 (d,2H), 7.38 (d, 2H), 7.25-7.31 (m, 2H), 7.15-7.21 (m, 1H), 7.08 (d, 1H),6.89 (d, 2H), 6.74 (br s, 1H), 3.63 (q, 2H), 3.22-3.31 (m, 10H),3.08-3.17 (m, 2H), 2.60-2.74 (m, 2H), 1.38 (s, 9H).

EXAMPLE 2363-(4′-((((4-(((1R)-2-((2-(dimethylamino)ethyl)(methyl)amino)-1-((phenylthio)methyl)ethyl)amino)-3-nitrophenyl)sulfonyl)amino)carbonyl)-2-methoxy-1,1′-biphenyl-4-yl)-N,N-dimethylpropanamideEXAMPLE 236A4′-(3-(dimethylamino)-3-oxopropyl)-2′-methoxy-1,1′-biphenyl-4-carboxylicacid

The desired product was prepared by substituting Example 427A forExample 1A in Example 1B.

EXAMPLE 236B3-(4′-((((4-(((1R)-2-((2-(dimethylamino)ethyl)(methyl)amino)-1-((phenylthio)methyl)ethyl)amino)-3-nitrophenyl)sulfonyl)amino)carbonyl)-2-methoxy-1,1′-biphenyl-4-yl)-N,N-dimethylpropanamide

The desired product was prepared by substituting Example 236A andExample 206C for Example 1B and Example 1C, respectively, in Example 1D.MS (ESI(−)) m/e 775 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ1.18 (s, 9H),1.79 (m, 2H), 2.35 (m, 6H), 2.62 (t, 2H), 3.28 (t, 2H), 3.54 (m, 4H),3.60 (dd, 2H), 3.75 (s, 3H), 6.88 (d, 1H), 6.94 (s, 1H), 6.98 (d, 1H),7.18 (d, 1H), 7.23 (m, 1H), 7.32 (t, 2H), 7.39 (d, 2H), 7.82 (d, 1H),7.89 (d, 2H), 8.20 (d, 2H), 8.48 (d, 1H).

EXAMPLE 237N-((2′-methoxy-4′-(3-(4-(methoxyacetyl)piperazin-1-yl)propyl-1,1′-biphenyl-4-yl)carbonyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting methoxyacetyl chloridefor dimethylcarbamic chloride in Example 200. MS (ESI(−)) m/e 760(M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ1.80 (m, 2H), 2.42 (m, 4H), 2.62 (t,2H), 3.26 (m, 4H), 3.28 (s, 3H), 3.40 (m, 4H), 3.48 (m, 2H), 3.60 (dd,2H), 3.75 (s, 3H), 4.08 (s, 2H), 6.86 (d, 1H), 6.95 (s, 1H), 6.99 (d,1H), 7.18 (d, 1H), 7.20 (dd, 1H), 7.31 (t, 2H), 7.40 (t, 4H), 7.88 (d,1H), 7.89 (d, 2H), 8.49 (d, 1H), 8.51 (t, 1H).

EXAMPLE 238N-((2′-methoxy-4′-(3-(4-(methylsulfonyl)piperazin-1-yl)propyl)-1,1′-biphenyl-4-yl)carbonyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting methanesulfonylchloride for dimethylcarbamic chloride in Example 200. MS (ESI(−)) m/e766 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ1.99 (m, 2H), 2.68 (m, 4H), 2.86(s, 3H), 2.96 (m, 4H), 3.08 (m, 4H), 3.30 (m, 4H), 3.77 (s, 3H), 4.08(m, 1H), 6.91 (d, 1H), 6.99 (s, 1H), 7.18 (m, 1H), 7.22 (dd, 1H), 7.28(m, 3H), 7.38 (d, 2H), 7.52 (d, 2H), 7.89 (d, 2H), 8.58 (d, 1H), 8.62(t, 1H).

EXAMPLE 239N-(4-(3,3-dimethylpiperidin-1-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamideEXAMPLE 239A ethyl 4-(3,3-dimethyl-2,6-dioxopiperidin-1-yl)benzoate

The desired product was prepared by substituting 2,2-dimethylglutaricanhydride for 3,3-dimethylglutaric anhydride in Example 119A. MS (DCI)m/e 307 (M+NH₄)⁺.

EXAMPLE 239B ethyl 4-(3,3-dimethylpiperidin-1-yl)benzoate

The desired product was prepared by substituting Example 239A forExample 119A in Example 119B. MS (DCI) m/e 262 (M+H)⁺.

EXAMPLE 239C 4-(3,3-dimethylpiperidin-1-yl)benzoic acid

The desired product was prepared by substituting Example 239B forExample 119B in Example 119C. MS (DCI) m/e 234 (M+H)⁺.

EXAMPLE 239DN-(4-(3,3-dimethylpiperidin-1-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 239C andExample 77B for Example 1B and Example 1C, respectively, in Example 1D.MS (ESI(−)) m/e 567 (M−M)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ11.92 (s, 1H),8.77 (t, 1H), 8.60 (d, 1H), 7.90 (dd, 1H), 7.70 (d, 2H), 7.37 (d, 2H),7.26 (t, 2H), 7.18 (m, 2H), 6.89 (d, 2H), 3.67 (m, 2H), 3.30 (m, 4H),3.09 (s, 2H), 1.59 (m, 2H), 1.38 (t, 2H), 0.89 (s, 6H).

EXAMPLE 2404-(((1R)-2-(dimethylamino)-1-((phenylthio)methyl)ethyl)amino)-N-((2′-methoxy-4′-(3-morpholin-4-yl-3-oxopropyl)-1,1′-biphenyl-4-yl)carbonyl)-3-nitrobenzenesulfonamideEXAMPLE 240A2′-methoxy-4′-(3-morpholin-4-yl-3-oxopropyl)-1,1′-biphenyl-4-carboxylicacid

The desired product was prepared by substituting Example 122M forExample 1A in Example 1B.

EXAMPLE 240B4-(((1R)-2-(dimethylamino)-1-((phenylthio)methyl)ethyl)amino)-N-((2′-methoxy-4′-(3-morpholin-4-yl-3-oxopropyl)-1,1′-biphenyl-4-yl)carbonyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 240A andExample 134D for Example 1B and Example 1C, respectively, in Example 1D.MS (ESI(−)) m/e 760 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ2.61 (m, 2H),2.66 (t, 2H), 2.84 (t, 2H), 3.31 (dd, 1H), 3.32 (s, 6H), 3.37 (dd, 1H),3.44 (m, 4H), 3.52 (m, 4H), 3.74 (s, 3H), 4.12 (m, 1H), 6.89 (d, 1H),6.94 (d, 1H), 6.99 (s, 1H), 7.16 (d, 1H), 7.20 (dd, 1H), 7.22 (dd, 2H),7.31 (d, 2H), 7.38 (d, 2H), 7.81 (d, 1H), 7.89 (d, 2H), 8.24 (d, 1H),8.44 (d, 1H).

EXAMPLE 2414-((3-(dimethylamino)-2-(phenylthio)propyl)amino)-N-((4′-fluoro-1,1′-biphenyl-4-yl)carbonyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 212C forExample 1C in Example 1D. MS (ESI(−)) m/e 607 (M−H)⁻; ¹H NMR (300 MHz,DMSO-d₆) δ8.80 (t, 1H), 8.52 (d, 1H), 7.93 (d, 2H), 7.87 (dd, 1H),7.76-7.70 (m, 2H), 7.60 (d, 2H), 7.51-7.47 (m, 2H), 7.35-7.25 (m, 5H),6.95 (d, 1H), 3.82-3.75 (m, 1H), 3.62-3.50 (m, 2H), 2.86-2.62 (m, 2H),2.41 (br s, 6H).

EXAMPLE 242N-((2′-methoxy-4′-(2-(4-methylpiperazin-1-yl)ethyl)-1,1′-biphenyl-4-yl)carbonyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamideEXAMPLE 242A methyl2′-methoxy-4′-(2-(4-methylpiperazin-1-yl)ethyl)-1,1′-biphenyl-4-carboxylate

The desired product was prepared by substituting N-methylpiperidine andExample 191A for dimethylamine and Example 134A, respectively, inExample 134B. MS (ESI(+)) m/e 369 (M+H)⁺.

EXAMPLE 242B2′-methoxy-4′-(2-(4-methylpiperazin-1-yl)ethyl)-1,1′-biphenyl-4-carbolicacid

The desired product was prepared by substituting Example 242A forExample 1A in Example 1B. MS (ESI(−)) m/e 353 (M−H)⁻.

EXAMPLE 242CN-((2′-methoxy-4′-(2-(4-methylpiperazin-1-yl)ethyl)-1,1′-biphenyl-4-yl)carbonyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 242B andExample 77B for Example 1B and Example 1C, respectively, in Example 1D.MS (ESI(−)) m/e 688 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ2.58 (s, 3H),2.82 (m, 2H), 3.40 (m, 4H), 2.98 (m, 6H), 3.15 (d, 2H), 3.28 (dd, 2H),3.76 (s, 3H), 4.05 (dd, 1H), 6.91 (d, 1H), 6.99 (d, 1H), 7.00 (s, 1H),7.18 (d, 1H), 7.20 (dd, 1H), 7.32 (t, 2H), 7.40 (t, 4H), 7.90 (m, 2H),8.49 (t, 1H), 8.51 (d, 1H).

EXAMPLE 2433-nitro-N-(4-(5-(3-oxo-3-piperidin-1-ylpropyl)quinolin-8-yl)benzoyl)-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting piperidine for1-methylpiperazine in Example 201. MS (ESI) m/e 722, 724 (M−H)⁻, (M+H)⁺;¹H NMR (300 MHz, DMSO-d₆) δ1.35 (m, 4H), 1.52 (m, 2H), 2.74 (t, 2H),3.27 (t, 2H), 3.29 (t, 2H), 3.35 (t, 2H), 3.43 (t, 2H) 3.61 (dt, 2H),6.99 (d, 1H), 7.20 (tt, 1H), 7.31 (td, 2H), 7.40 (dd, 2H), 7.52-7.60 (m,4H), 7.67 (d, 1H), 7.89 (dd, 1H), 7.95 (d, 2H), 8.51 (t, 1H), 8.52 (d,1H), 8.56 (dd, 1H), 8.88 (dd, 1H).

EXAMPLE 244N-(2-(dimethylamino)ethyl)-3-(8-(4-((((3-nitro-4-((2-(phenylthio)ethyl)amino)phenyl)sulfonyl)amino)carbonyl)phenyl)quinolin-5-yl)propanamide

The desired product was prepared by substitutingN,N-dimethylethylenediamine for 1-methylpiperazine in Example 201. MS(ESI) m/e 725, 727 (M−H)⁻, (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ2.56 (t,2H), 2.68 (s, 6H), 2.97 (t, 2H), 3.08 (q, 2H), 3.08 (q, 2H), 3.27 (t,2H), 3.36 (t, 2H), 3.61 (dt, 2H), 7.00 (d, 1H), 7.20 (tt, 1H), 7.31 (t,2H), 7.40 (d, 2H), 7.51 (d, 1H), 7.57 (d, 2H), 7.60 (dd, 1H), 7.68 (d,1H), 7.89 (dd, 1H), 7.96 (d, 2H), 8.11 (t, 1H), 8.52 (t, 1H), 8.53 (d,1H), 8.58 (dd, 1H), 8.90 (dd, 1H).

EXAMPLE 245N-((4′-fluoro-1,1′-biphenyl-4-yl)carbonyl)-4-((2-morpholin-4-yl-1-((phenylthio)methyl)ethyl)amino)-3-nitrobenzenesulfonamideEXAMPLE 245A4-((2-morpholin-4-yl-1-((phenylthio)methyl)ethyl)amino)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 180B forExample 122F in Example 122G. MS (ESI(+)) m/e 453 (M+H)⁺.

EXAMPLE 245BN-((4′-fluoro-1,1′-biphenyl-4-yl)carbonyl)-4-((2-morpholin-4-yl-1-((phenylthio)methyl)ethyl)amino)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 245A forExample 1C in Example 1D. MS (ESI(−)) m/e 649 (M−H)⁻; ¹H NMR (400 MHz,DMSO-d₆) δ8.55 (d, 1H), 8.45 (d, 1H), 7.97 (d, 2H), 7.88 (dd, 1H), 7.75(m, 5H), 7.30 (m, 4H), 7.15 (m, 3H), 4.30 (m, 1H), 3.55 (t, 4H), 3.42(dd, 1H), 3.31 (dd, 1H), another 4 protons were buried under solventpeaks.

EXAMPLE 2463-(2-methoxy-4′-((((4-(((1R)-2-morpholin-4-yl-1-((phenylthio)methyl)ethyl)amino)-3-nitrophenyl)sulfonyl)amino)carbonyl)-1,1′-biphenyl-4-yl)-N,N-dimethylpropanamide

The desired product was prepared by substituting Example 236A andExample 146C for Example 1B and Example 1C, respectively, in Example 1D.MS (ESI(−)) m/e 760 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ2.36 (t, 2H),2.44 (t, 2H), 2.62 (dd, 4H), 2.81 (dd, 2H), 2.82 (s, 3H), 2.96 (s, 3H),3.31 (m, 1H), 3.41 (dd, 1H), 3.52 (dd, 4H), 3.74 (s, 3H), 4.15 (m, 1H),6.89 (d, 1H), 6.94 (d, 1H), 6.99 (s, 1H), 7.18 (d, 1H), 7.20 (dd, 1H),7.32 (t, 2H), 7.45 (m, 4H), 7.81 (dd, 1H), 7.89 (d, 2H), 8.32 (d, 1H),8.48 (d, 1H).

EXAMPLE 247N-(4-(3,3-dimethylpyrrolidin-1-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamideEXAMPLE 247A methyl 4-(3,3-dimethyl-2,5-dioxopyrrolidin-1-yl)benzoate

The desired product was prepared by substituting methyl 4-aminobenzoateand 2,2-dimethylsuccinic anhydride for ethyl 4-aminobenzoate and3,3-dimethylglutaric anhydride, respectively, in Example 119A. MS (DCI)m/e 262 (M+H)⁺.

EXAMPLE 247B methyl 4-(3,3-dimethylpyrrolidin-1-yl)benzoate

The desired product was prepared by substituting Example 247A forExample 119A in Example 119B. MS (DCI) m/e 234 (M+H)⁺.

EXAMPLE 247C 4-(3,3-dimethylpyrrolidin-1-yl)benzoic acid

The desired product was prepared by substituting Example 247B forExample 119B in Example 119C. MS (DCI) m/e 220 (M+H)⁺.

EXAMPLE 247DN-(4-(3,3-dimethylpyrrolidin-1-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 247C andExample 77B for Example 1B and Example 1C, respectively, in Example 1D.MS (ESI(−)) m/e 553 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ11.87 (s, 1H),8.76 (t, 1H), 8.60 (d, 1H), 7.91 (dd, 1H), 7.72 (d, 2H), 7.37 (d, 2H),7.26 (t, 2H), 7.18 (m, 2H), 6.50 (d, 2H), 3.67 (m, 2H), 3.38 (t, 2H),3.30 (m, 2H), 3.07 (s, 2H), 1.77 (t, 2H), 1.09 (s, 6H).

EXAMPLE 248N-((2′-methoxy-4′-(3-(4-methylpiperazin-1-yl)propyl)-1,1′-biphenyl-4-yl)carbonyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamideEXAMPLE 248A methyl2′-methoxy-4′-(3-(4-methylpiperazin-1-yl)propyl)-1,1′-biphenyl-4-carboxylate

A solution of Example 362A (1.00 g, 2.52 mmol) in THF (5 mL) at roomtemperature was slowly treated with 1M BH₃ in THF (7.57 mL, 7.57 mmol),stirred for 16 hours, quenched with methanol (30 mL) and water (5 mL),treated with concentrated HCl (1 mL), heated to 60° C., and stirred for2 hours. The mixture was treated with 1M NaOH (50 mL) and extracted with80:20:0.5 dichloromethane/methanol/concentrated ammonium hydroxide(3×250 mL). The combined extracts were washed with brine (50 mL), andconcentrated. The concentrate was purified by flash columnchromatography on silica gel with 80:20:0.5dichloromethane/methanol/concentrated ammonium hydroxide to provide thedesired product.

EXAMPLE 248B2′-methoxy-4′-(3-(4-methylpiperazin-1-yl)propyl)-1,1′-biphenyl-4-carboxylicacid

The desired product was prepared by substituting Example 248A forExample 1A in Example 1B.

EXAMPLE 248CN-((2′-methoxy-4′-(3-(4-methylpiperazin-1-yl)propyl)-1,1′-biphenyl-4-yl)carbonyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 248B andExample 77B for Example 1B and Example 1C, respectively, in Example 1D.MS (ESI) m/e 702, 704 (M−H)⁻, (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ1.87(m, 2H), 2.23 (s, 3H), 2.57 (m, 8H), 2.63 (t, 2H), 3.06 (q, 2H), 3.26(t, 2H), 3.60 (dt, 2H), 3.75 (s, 3H), 6.87 (d, 1H), 6.95 (s, 1H), 7.00(d, 1H), 7.19 (tt, 1H), 7.21 (d, 2H), 7.30 (td, 2H), 7.47-7.53 (m, 3H),7.88 (d, 3H), 8.50 (d, 1H), 8.53 (d, 1H).

EXAMPLE 2493-nitro-4-((2-(phenylthio)ethyl)amino)-N-(4-(thien-3-ylmethoxy)benzoyl)benzenesulfonamide

The desired product was prepared by substituting 3-thiophenemethanol for4-butylbenzyl alcohol in Example 209. MS (ESI) m/e 568, 570 (M−H)⁻,(M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ3.27 (t, 2H), 3.62 (dt, 2H), 5.12 (s,2H), 6.97 (d, 2H), 7,06 (d, 1H), 7.18 (t, 2), 7.28 (t, 2H), 7.38 (d,2H), 7.54 (dd, 1H), 7.58 (s, 1H), 7.83 (d, 2H), 7.87 (dd, 1H), 8.54 (d,1H), 8.62 (t, 1H).

EXAMPLE 250N-(4-(4-(3-(4-methylpiperidin-1-yl)propyl)piperidin-1-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

A solution Example 226 (20 mg, 0.03 mmol) and 4-methylpiperidine (0.02mL, 0.17 mmol), and methanol (0.4 mL) at room temperature was treatedwith NaCNBH₃ (5.5 mg, 0.08 mmol) and acetic acid (1 drop), stirred for18 hours, diluted with dichloromethane, washed with saturated NaHCO₃ andbrine, dried (MgSO₄), filtered, and concentrated. The concentrate waspurified by reverse phase chromatography, eluting with 0-100%CH₃CN/water containing 0.1% TFA to provide the desired product. MS (ESI)m/e 678 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ11.87 (s, 1H), 8.79 (t, 1H),8.60 (d, 1H), 7.91 (dd, 1H), 7.72 (d, 2H), 7.35 (d, 2H), 7.28-7.15 (m,4H), 6.93 (d, 2H), 3.67 (m, 2H), 3.38 (t, 2H), 3.29 (m, 2H), 2.28 (m,1H), 1.85-1.60 (m, 8H), 1.36-1.00 (m, 6H), 0.92 (d, 3H).

EXAMPLE 2513-nitro-N-(4-(2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)benzoyl)-4-((2-(phenylthio)ethyl)amino)benzenesulfonamideEXAMPLE 251A 6-bromo-1,3-benzoxazol-2(3H)-one

A mixture of 2-benzoxazolinone (3.00 g, 22.2 mmol),1,3-dibromo-5,5-dimethylhydantoin (3.49 g, 12.2 mmol), andtrifluoromethanesulfonic acid (5.00 g, 33.3 mmol) in dichloromethane(100 mL) at room temperature was protected from light, stirred for 1hour, and concentrated. The concentrate was purified by flash columnchromatography on silica gel with 50% ethyl acetate/hexanes to providethe desired product.

EXAMPLE 251B methyl 4-(2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)benzoate

The desired product was prepared by substituting Example 251A forExample 5A in Example 5B.

EXAMPLE 251C 4-(2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)benzoic acid

The desired product was prepared by substituting Example 251B forExample 1A in Example 1B.

EXAMPLE 251D3-nitro-N-(4-(2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)benzoyl)-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 251C andExample 77B for Example 1B and Example 1C, respectively, in Example 1D.MS (ESI) m/e 589 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ3.27 (t, 2H), 3.61(dt, 2H), 7.01 (d, 1H), 7.15 (d, 1H), 7.18 (tt, 1H), 7.29 (td, 2H), 7.39(d, 2H), 7.48 (dd, 1H), 7.62 (d, 2H), 7.65 (d, 1H), 7.89 (dd, 1H), 7.94(d, 2H), 8.52 (d, 1H), 8.53 (t, 1H), 11.70 (s, 1H).

EXAMPLE 252N-(4-(6-chloropyridin-3-yl)benzoyl)-3-nitro-4-(((4-(phenylthio)piperidin-4-yl)methyl)amino)benzenesulfonamideEXAMPLE 252A tert-butyl 4-cyano-4-(phenylthio)piperidine-1-carboxylate

A solution of diisopropylamine (3.36 mL, 24 mmol) in THF (20 mL) at −78°C. was slowly treated with 2.5M n-butyllithium (7.2 mL, 18 mmol) inhexanes, warmed to 0° C. for 15 minutes, cooled to −78° C., treatedslowly with a solution of N-BOC-4-cyanopiperidine (2.5 g, 12 mmol) inTHF (10 mL), stirred for 30 minutes, and treated with a solution ofPhSSPh (5.24 g, 24 mmol) in THF (20 mL). The mixture was stirred for 2hours, warmed to room temperature, and quenched with saturated NH₄Cl (50mL). The mixture was extracted with ethyl acetate (3×50 mL) and thecombined extracts were washed with water and brine, dried (Na₂SO₄),filtered, and concentrated. The concentrate was purified by flash columnchromatography on silica gel with 3:1 hexanes/ethyl acetate to providethe desired product. MS (ESI) m/e 319 (M+H)⁺.

EXAMPLE 252B tert-butyl4-(aminomethyl)-4-(phenylthio)piperidine-1-carboxylate

A solution of Example 252A (1.0 g, 3.1 mmol) in THF (5 mL) at 0° C. wastreated dropwise with 1M LiAlH₄ in THF (3 mL), warmed to roomtemperature, stirred for 2 hours, quenched with methanol (1 mL), treatedwith 1N NaOH (50 mL), and extracted with ethyl acetate (3×100 mL). Thecombined extracts were washed with water and brine, dried (Na₂SO₄),filtered, and concentrated to provide the desired product. MS (APCI) m/e323(M+H)⁺.

EXAMPLE 252C tert-butyl4-(((4-(aminosulfonyl)-2-nitrophenyl)amino)methyl)-4-(phenylthio)piperidine-1-carboxylate

A mixture of Example 252B (1.0 g, 3.1 mmol), Example 122C (0.683 g, 3.1mmol), and diisopropylethylamine (2 mL) in DMSO (10 mL) was heated to50° C. for 18 hours, diluted with ethyl acetate (100 mL), washed withwater and brine, dried (Na₂SO₄), filtered, and concentrated. Theconcentrate was purified by flash column chromatography on silica gelwith 1:1 hexanes/ethyl acetate to provide the desired product. MS(ESI(−)) m/e 521 (M−H)⁻.

EXAMPLE 252D methyl 4-(6-methoxypyridin-3-yl)benzoate

A mixture of 5-bromo-2-methoxypyridine (2.93 g, 10 mmol),4-methylcarboxybenzeneboronic acid (1.80 g, 10 mmol), Pd(Ph₃P)₄ (0.346g, 0.3 mmol) and CsF (1.52 g, 10 mmol) in DME (60 mL) and methanol (30mL) was heated to reflux for 18 hours and concentrated. The concentratewas dissolved in water (50 mL) and ethyl acetate (300 mL) and theorganic phase was washed with water (2×50 mL) and brine (50 mL), dried(Na₂SO₄), filtered, and concentrated. The concentrate was purified byflash column chromatography on silica gel with 3:1 hexanes/ethyl acetateto provide the desired product. MS (APCI) m/e 278, 280 (M−H)⁻, (M+H)⁺.

EXAMPLE 252E methyl 4-(6-hydroxypyridin-3-yl)benzoate

A solution of Example 252D (0.5 g, 2.2 mmol) in dichloromethane at −78°C. was treated with 1M BBr₃ in dichloromethane (15 mL), warm to roomtemperature, and stirred for 18 hours. The reaction was quenched withmethanol (5 mL), diluted with dichloromethane (100 mL), washed withwater (30 mL), brine (30 mL), dried (Na₂SO₄), filtered, andconcentrated. The concentrate was purified by flash columnchromatography on silica gel with 2:1 hexanes/ethyl acetate to providethe desired product. MS (ESI) m/e 228, 230 (M−H)⁻, (M+H)⁺.

EXAMPLE 252F methyl 4-(6-chloropyridin-3-yl)benzoate

A solution of Example 252E (1.2 g, 5 mmol) in POCl₃ (30 mL) was heatedto reflux for 30 minutes. The excess POCl₃ was removed under vacuum andthe remaining product was purified by flash column chromatography onsilica gel with 4:1 ethyl acetate/hexanes to provide the desiredproduct. MS (ESI) m/e 248 (M+H)⁺.

EXAMPLE 252G 4-(6-chloropyridin-3-yl)benzoic acid

A solution of Example 252F (1.56 g, 6.4 mmol) in THF (30 mL) at roomtemperature treated with a solution of LiOH.H₂O (0.537 g, 12.8 mmol) inwater (5 mL), heated to reflux for 4 hours, cooled to room temperatureand concentrated. The mixture was neutralized with 1N HCl and extractedethyl acetate (3×50 mL). The combined extracts were washed with brine,dried (Na₂SO₄), filtered, and concentrated to provide the desiredproduct. MS (APCI) m/e 234 (M+H)⁺.

EXAMPLE 252HN-(4-(6-chloropyridin-3-yl)benzoyl)-3-nitro-4-(((4-(phenylthio)piperidin-4-yl)methyl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 252C andExample 252G for Example 124E and Example 257C, respectively, in Example124F. MS (ESI(−)) m/e 636 (M−H)⁻; ¹H NMR (500 MHz, DMSO-d₆) δ9.10 (m,1H), 8.98 (t, 1H), 8.93 (m, 1H), 8.81 (dd, 1H), 8.74 (d, 1H), 8.24 (dd,1H), 8.01 (d, 2H), 7.90 (d, 2H), 7.64 (d, 1H), 7.54 (dt, 2H), 7.48 (tt,1H), 7.41 (td, 2H), 7.33 (d, 1H), 3.40 (d, 2H), 3.23 (m, 4H), 1.97-1.82(m, 4H).

EXAMPLE 2533-nitro-4-(((4-(phenylthio)piperidin-4-yl)methyl)amino)-N-(4-(5-(trifluoromethyl)pyridin-2-yl)benzoyl)benzenesulfonamideEXAMPLE 253A methyl 4-(5-(trifluoromethyl)pyridin-2-yl)benzoate

The desired product was prepared by substituting2-chloro-5-trifluoromethylpyridine for 5-bromo-2-methoxypyridine inExample 252D. MS (ESI(+)) m/e 282 (M+H)⁺.

EXAMPLE 253B 4-(5-(trifluoromethyl)pyridin-2-yl)benzoic acid

The desired product was prepared by substituing Example 253A for Example252F in Example 252G. MS (ESI(+)) m/e 268 (M+H)⁺.

EXAMPLE 253C3-nitro-4-(((4-(phenylthio)piperidin-4-yl)methyl)amino)-N-(4-(5-(trifluoromethyl)pyridin-2-yl)benzoyl)benzenesulfonamide

The desired product was prepared by substituting Example 252C andExample 253B for Example 124E and Example 257C, respectively, in Example124F. MS (ESI(−)) m/e 636 (M−H)⁻; ¹H NMR (500 MHz, DMSO-d₆) δ9.09 (d,1H), 9.08 (m, 1H), 8.98 (t, 1H), 8.89 (m, 1H), 8.74 (d, 1H), 8.34 (dd,1H), 8.30 (d, 1H), 8.29 (d, 2H), 8.04 (d, 2H), 8.01 (dd, 1H), 7.54 (dt,2H), 7.48 (tt, 1H), 7.41 (td, 2H), 7.33 (d, 1H), 3.40 (d, 2H), 3.23 (m,4H), 1.97-1.82 (m, 4H).

EXAMPLE 254N-(4-(5-chloropyridin-2-yl)benzoyl)-3-nitro-4-(((4-(phenylthio)piperidin-4-yl)methyl)amino)benzenesulfonamideEXAMPLE 254A methyl 4-(5-chloropyridin-2-yl)benzoate

The desired product was prepared by substituting 2,5-dichloropyridinefor 5-bromo-2-methoxypyridine in Example 252D. MS (ESI(+)) m/e 248(M+H)⁺.

EXAMPLE 254B 4-(5-chloropyridin-2-yl)benzoic acid

The desired product was prepared by substituting Example 254A forExample 252F in Example 252G. MS (ESI(+)) m/e 234 (M+H)⁺.

EXAMPLE 254CN-(4-(5-chloropyridin-2-yl)benzoyl)-3-nitro-4-(((4-(phenylthio)piperidin-4-yl)methyl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 252C andExample 254B for 124E and 257C, respectively, in Example 124F. MS(ESI(−)) m/e 636 (M−H)⁻; ¹H NMR (500 MHz, DMSO-d₆) δ9.05 (m, 1H), 8.98(t, 1H), 8.85 (m, 1H), 8.74 (m, 2H), 8.21 (d, 2H), 8.11 (d, 1H), 8.06(dd, 1H), 8.00 (d, 2H), 7.54 (dt, 2H), 7.48 (tt, 1H), 7.41 (td, 2H),7.32 (d, 1H), 3.40 (d, 2H), 3.23 (m, 4H), 1.97-1.82 (m, 4H).

EXAMPLE 2554-((2-adamantylmethyl)amino)-3-nitro-N-(4-quinolin-8-ylbenzoyl)benzenesulfonamideEXAMPLE 255A4-((1-adamantylmethyl)amino)-3-nitro-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl)benzenesulfonamide

The desired product was prepared by substituting Example 28A for Example3A in Example 3C.

EXAMPLE 255B4-((2-adamantylmethyl)amino)-3-nitro-N-(4-quinolin-8-ylbenzoyl)benzenesulfonamide

The desired product was prepared by substituting Example 255A and8-bromoquinoline for Example 108A and Example 389A, respectively, inExample 389B. MS (ESI(−)) m/e 595 (M−H)⁻; ¹H NMR (300 MHz, methanol-d₄)δ8.81 (m, 2H), 8.52 (7, 1H), 8.39 (dd, 1H), 8.16 (d, 2H), 8.03 (d, 1H),7.95 (d, 1H), 7.74 (d, 1H), 7.68 (d, 1H), 7.63 (d, 2H), 7.52 (dd, 2H),7.13 (d, 1H), 3.12 (d, 2H), 1.98 (m, 3H), 1.72-1.55 (m, 12H).

EXAMPLE 256N-(4-(2-methylquinolin-8-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamideEXAMPLE 256A 2-methylquinolin-8-yl trifluoroacetate

The desired product was prepared by substituting8-hydroxy-2-methylquinoline for vanillin in Example 122H.

EXAMPLE 256BN-(4-(2-methylquinolin-8-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 256A forExample 389A in Example 389B. MS (ESI(−)) m/e 597 (M−H)⁻; ¹H NMR (400MHz, DMSO-d₆) δ8.57 (m, 2H), 8.29 (d, 1H), 7.94 (m, 4H), 7.72 (m, 1H),7.65 (d, 2H), 7.59 (t, 1H), 7.44 (d, 1H), 7.40 (m, 2H), 7.30 (t, 2H),7.20 (tt, 1H), 7.06 (d, 1H), 3.63 (q, 2H), 3.26 (t, 2H), 2.59 (s, 3H).

EXAMPLE 257 tert-butyl(5R)-5-((4-(((4-(8-azaspiro(4.5)dec-8-yl)benzoyl)amino)sulfonyl)-2-nitrophenyl)amino)-6-(phenylthio)hexylcarbamateEXAMPLE 257A methyl 4-(7,9-dioxo-8-azaspiro(4.5)dec-8-yl)benzoate

The desired product was prepared by substituting methyl 4-aminobenzoateand 3,3-tetramethyleneglutaric anhydride for ethyl 4-aminobenzoate and3,3-dimethylglutaric anhydride, respectively, in Example 119A. MS (DCI)m/e 302 (M+H)⁺.

EXAMPLE 257B methyl 4-(8-azaspiro(4.5)dec-8-yl)benzoate

The desired product was prepared by substituting Example 257A forExample 119A in Example 119B. MS (DCI) m/e 274 (M+H)⁺.

EXAMPLE 257C 4-(8-azaspiro(4.5)dec-8-yl)benzoic acid

The desired product was prepared by substituting Example 257B forExample 119B in Example 119C. MS (DCI) m/e 260 (M+H)⁺.

EXAMPLE 257D tert-butyl(5R)-5-((4-(((4-(8-azaspiro(4.5)dec-8-yl)benzoyl)amino)sulfonyl)-2-nitrophenyl)amino)-6-(phenylthio)hexylcarbamate

The desired product was prepared by substituting Example 257C andExample 124C for Example 1B and Example 1C, respectively, in Example 1D.MS (ESI(+)) m/e 766; ¹H NMR (300 MHz, DMSO-d₆) δ11.96 (s, 1H), 8.52 (d,1H), 8.29 (d, 1H), 7.83 (dd, 1H), 7.74 (d, 2H), 7.24 (d, 2H), 7.18-7.08(m, 4H), 6.91 (d, 2H), 6.72 (t, 1H), 4.04 (s, 1H), 3.98 (t, 1H), 2.86(m, 2H), 1.72 (m, 2H), 1.59 (m, 4H), 1.45 (m, 8H), 1.31 (s, 9H).

EXAMPLE 258N-(4-(3-azabicyclo(3.1.0)hex-3-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamideEXAMPLE 258A methyl 4-(2,4-dioxo-3-azabicyclo(3.1.0)hex-3-yl)benzoate

The desired product was prepared by substituting methyl 4-aminobenzoateand 3-oxabicyclo(3.1.0)hexane-2,4-dione for ethyl 4-aminobenzoate and3,3-dimethylglutaric anhydride, respectively, in Example 119A. MS (DCI)m/e 263 (M+NH₄)⁺.

EXAMPLE 258B methyl 4-(3-azabicyclo(3.1.0)hex-3-yl)benzoate

The desired product was prepared by substituting Example 258A forExample 119A in Example 119B. MS (DCI) m/e 218 (M+H)⁺.

EXAMPLE 258C 4-(3-azabicyclo(3.1.0)hex-3-yl)benzoic acid

The desired product was prepared by substituting Example 258B forExample 119B in Example 119C. MS (DCI) m/e 204 (M+H)⁺.

EXAMPLE 258DN-(4-(3-azabicyclo(3.1.0)hex-3-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 258C andExample 77B for Example 1B and Example 1C, respectively, in Example 1D.MS (ESI(+)) m/e 561 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ11.91 (s, 1H),8.74 (t, 1H), 8.58 (d, 1H), 7.90 (dd, 1H), 7.71 (d, 2H), 7.37 (d, 2H),7.27 (t, 2H), 7.18 (m, 2H), 6.52 (d, 2H), 3.36 (m, 2H), 3.51 (d, 2H),3.25 (m, 4H), 1.71 (m, 2H), 0.75 (m, 1H), 0.18 (m, 1H).

EXAMPLE 259N-(4-(4-ethyl-4-methylpiperidin-1-yl)benzoyl-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 123C andExample 77B for Example 1B and Example 1C, respectively, in Example 1D.MS (ESI(−)) m/e 581 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ11.96 (s, 1H),8.77 (t, 1H), 8.60 (d, 1H), 7.91 (dd, 1H), 7.73 (d, 2H), 7.37 (d, 2H),7.26 (t, 2H), 7.18 (m, 2H), 6.91 (d, 2H), 3.67 (m, 2H), 3.45 (m, 2H),3.30 (m, 2H), 3.20 (m, 2H), 1.36 (m, 3H), 1.29 (m, 3H), 0.90 (s, 3H),0.80 (t, 3H).

EXAMPLE 2603-nitro-N-(4-(2-(2-phenylethyl)-1,3-benzothiazol-5-yl)benzoyl)-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting benzyl bromide forallyl bromide in Example 213. MS (ESI) m/e 693, 695 (M−H)⁻, (M+H)⁺; ¹HNMR (300 MHz, DMSO-d₆) δ3.18 (t, 2H), 3.29 (t, 2H), 3.47 (t, 2H), 3.64(dt, 2H), 7.11 (d, 1H), 7.19 (dt, 2H), 7.25-7.34 (m, 6H), 7.39 (dd, 2H),7.75 (dd, 1H), 7.81 (d, 2H), 7.92 (dd, 1H), 7.98 (d, 2H), 8.12 (d, 1H),8.26 (d, 1H), 8.57 (d, 1H), 8.65 (t, 1H).

EXAMPLE 261 tert-butyl(5R)-5-((4-(((4-(4,4-dimethylpiperidin-1-yl)benzoyl)amino)sulfonyl)-2-nitrophenyl)amino)-6-(phenylthio)hexylcarbamate

The desired product was prepared by substituting Example 119C andExample 124C, for Example 1B and Example 1C, respectively, in Example1D. MS(ESI(+)) m/e 740 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ11.96 (s, 1H),8.49 (d, 1H), 8.23 (d, 1H), 7.81 (dd, 1H), 7.73 (d, 2H), 7.26 (d, 2H),7.21-7.11 (m, 3H), 7.04 (d, 1H), 6.87 (d, 2H), 6.72 (t, 1H), 4.00 (m,2H), 3.28 (m, 6H), 1.71 (m, 2H), 1.35 (m, 8H), 1.32 (s, 9H), 0.94 (s,6H).

EXAMPLE 2624-(((1R)-5-amino-1-((phenylthio)methyl)pentyl)amino)-N-((2′-methoxy-4′-(3-morpholin-4-yl-3-oxopropyl)-1,1′-biphenyl-4-yl)carbonyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 122M forExample 122N in Example 194. MS (ESI(−)) m/e 774 (M−H)⁻; ¹H NMR(300MHz,DMSO-d₆), δ12.50 (br s, 1H), 8.55 (d, 1H), 8.35 (br d, 1H), 7.90 (d,2H), 7.85 (dd, 1H), 7.70 (br s, 2H), 7.58 (d, 2H), 7.30-7.12 (m, 7H),7.00 (d, 1H), 6.89 (dd, 1H), 4.10 (m, 1H), 3.75 (s, 3H), 3.50(m, 4H),3.45 (m, 4H), 3.35 (m, 2H), 2.85 (t, 2H), 2.75 (m, 2H), 2.70 (t, 2H),1.75 (m, 2H), 1.50 (m, 2H), 1.40 (m, 2H).

EXAMPLE 2632-(4′-((((4-(((1R)-5-amino-1-((phenylthio)methyl)pentyl)amino)-3-nitrophenyl)sulfonyl)amino)carbonyl)-2-methoxy-1,1′-biphenyl-4-yl)-N,N-dimethylacetamide

The desired product was prepared by substituting Example 441A forExample 122N in Example 194. MS (ESI(−)) m/e M−H)⁻; ¹H NMR (300 MHz,DMSO-d₆) δ12.5 (br s, 1H), 8.55 (d, 1H), 8.35 (br d, 1H), 7.90 (d, 2H),7.85 (dd, 1H), 7.70 (br s, 2H), 7.58 (d, 2H), 7.25 (dd, 1H), 7.20 (d,1H), 7.0-7.12 (m, 5H), 7.00 (d, 1H), 6.89 (dd, 1H), 4.10 (m, 1H), 3.75(s, 3H), 3.72 (s, 2H), 3.35 (m, 2H), 3.04 (s, 3H), 2.85 (s, 3H), 2.75(m, 2H), 1.75 (m, 2H), 1.50 (m, 2H), 1.40 (m, 2H).

EXAMPLE 2644-((cyclohexylmethyl)amino)-3-nitro-N-(4-quinolin-8-ylbenzoyl)benzenesulfonamideEXAMPLE 264A methyl 4-quinolin-8-ylbenzoate

The desired product was prepared by substituting 8-bromoquinoline forExample 5A in Example 5B.

EXAMPLE 264B 4-quinolin-8-ylbenzoic acid

The desired product was prepared by substituting Example 264A forExample 1A in Example 1B.

EXAMPLE 264C4-((cyclohexylmethyl)amino)-3-nitro-N-(4-quinolin-8-ylbenzoyl)benzenesulfonamide

The desired product was prepared by substituting Example 264B andExample 21B for Example 1B and Example 1C, respectively, in Example 1D.MS (ESI(−)) m/e 543 (M−H)⁻; ¹H NMR (500 MHz, DMSO-d₆) δ8.91 (dd, 1H),8.53 (d, 1H), 8.43 (dd, 1H), 8.40 (t, 1H), 8.00 (d, 1H), 7.97 (d, 2H),7.92 (dd, 1H), 7.77 9dd, 1H), 7.68 (t, 1H), 7.60 9d, 2H), 7.56 (dd, 1H),7.08 (d, 1H), 3.25 (t, 2H), 1.80-1.60 (m, 6H), 1.25-1.12 (m, 3H), 1.00(m, 2H).

EXAMPLE 265N-(4-(4-(4-fluorophenyl)piperazin-1-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamideEXAMPLE 265A ethyl 4-(4-(4-fluorophenyl)piperazin-1-yl)benzoate

The desired product was prepared by substituting4-fluorophenyl-1-piperazine for Example 131A in Example 131B. MS(ESI(+)) m/e 329 (M+H)⁺.

EXAMPLE 265B 4-(4-(4-fluorophenyl)piperazin-1-yl)benzoic acid

The desired product was prepared by substituting Example 265A forExample 131B in Example 131C. MS (ESI(−)) m/e 299 (M−H)⁻.

EXAMPLE 265CN-(4-(4-(4-fluorophenyl)piperazin-1-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 265B andExample 77B for Example 1B and Example 1C, respectively, in Example 1D.MS (ESI(−)) m/e 634 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ12.05 (br s, 1H),8.78 (t, 1H), 8.60 (d, 1H), 7.91 (dd, 1H), 7.77 (d, 2H), 7.35-7.39 (m,2H), 6.97-7.29 (m, 10H), 3.67(q, 2H), 3.41-3.52 (m, 4H), 3.25-3.31 (m,2H), 3.17-3.23 (m, 4H).

EXAMPLE 266N-(4-(8-azaspiro(4.5)dec-8-yl)benzoyl)-4-((2-methyl-2-(phenylthio)propyl)amino)-3-nitrobenzenesulfonamideEXAMPLE 266A 2-methyl-2-(phenylthio)propanenitrile

A solution of isobutyronitrile (1.382 g, 1.82 mL, 20 mmol) in THF (12mL) at −78° C. was treated dropwise with 1.5M LDA.THF in cyclohexane (14mL, 21 mmol), stirred for 30 minutes, treated with PhSSPh (4.36 g, 20mmol), stirred for 30 minutes, warmed to room temperature, quenched withNaHCO₃, and extracted with diethyl ether. The combined extracts weredried (MgSO₄), filtered, and concentrated. The concentrate was purifiedby flash column chromatography on silica gel with 0-10% ethylacetate/pentane to provide the desired product. MS (DCI(+)) m/e 195(M+18)⁺.

EXAMPLE 266B 2-methyl-2-(phenylthio)propan-1-amine

A solution of Example 266A (0.5 g, 2.82 mmol) in THF at room temperaturewas treated with 1M BH₃.THF (15 mL), stirred for 18 hours, quenched withmethanol (5 mL), and concentrated. The concentrate was treated with 2MHCl (50 mL) and concentrated. The concentrate was partitioned betweendichloromethane and saturated sodium bicarbonate, and the organic phasewas dried (MgSO₄), filtered, and concentrated to provide the desiredproduct. MS (DCI(+)) m/e 182 (M+H)⁺.

EXAMPLE 266C4-((2-methyl-2-(phenylthio)propyl)amino)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 266B forExample 195A in Example 195B. MS (ESI(−)) m/e 380 (M−H)⁻.

EXAMPLE 266DN-(4-(8-azaspiro(4.5)dec-8-yl)benzoyl)-4-((2-methyl-2-(phenylthio)propyl)amino)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 257C andExample 266C for Example 1B and Example 1C, respectively, in Example 1D.MS (ESI(−)) m/e 621 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ8.84 (t, 1H),8.63 (d, 1H), 7.92 (dd, 1H), 7.72 (d, 2H), 7.51-7.35 (m, 5H), 7.16 (d,1H), 6.87 (d, 2H), 3.32-3.24 (m, 6H), 1.62-1.57 (m, 4), 1.51-1.40 (m,8H), 1.31 (s, 6H).

EXAMPLE 267N-(4-(8-azaspiro(4.5)dec-8-yl)benzoyl)-4-((1,1-dimethyl-2-(phenylthio)ethyl)amino)-3-nitrobenzenesulfonamideEXAMPLE 267A 2-methyl-1-(phenylthio)propan-2-amine

A mixture of anhydrous CeCl₃ (7.64 g, 31 mmol) in THF (40 ML) at roomtemperature was stirred for 2 hours, cooled to −78° C., treated dropwisewith 1.4M methyllithium in diethyl ether (21.4 mL, 30 mmol), stirred for1 hour, treated with PhSCH₂CN (1.492 g, 10 mmol, 1.3 mL), stirred for 2hours, warmed to −35° C. over 1 hour, quenched with NH₄OH, warmed toroom temperature, and filtered through diatomaceous earth (Celite®). Thepad was washed with dichloromethane and the organic phase was dried over(MgSO₄), filtered, and concentrated. The concentrate was dissolved in 2MHCl, washed with dichloromethane (2×), and the aqueous phase wasconcentrated. The concentrate was treated with dichloromethane andneutralized with saturated sodium bicarbonate. The organic phase wasdried (MgSO₄), filtered, and concentrated to provide the desiredproduct. MS (DCI(+)) m/e 182 (M+H)⁺.

EXAMPLE 267B4-((1,1-dimethyl-2-(phenylthio)ethyl)amino)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 267A forExample 195A in Example 195B. MS (ESI(−)) m/e 380 (M−H)⁻.

EXAMPLE 267CN-(4-(8-azaspiro(4.5)dec-8-yl)benzoyl)-4-((1,1-dimethyl-2-(phenylthio)ethyl)amino)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 257C andExample 267B for Example 1B and Example 1C, respectively, in Example 1D.MS (ESI(−)) m/e 621 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ11.98 (br s, 1H),8.50-8.48 (m, 2H), 7.84 (dd, 1H), 7.75 (d, 2H), 7.34 (d, 1H), 7.29-7.24(m, 2H), 7.08-6.98 (m, 2H), 6.98 (d, 1H), 6.89 (d, 2H), 3.54 (s, 2H),3.32-3.24 (m, 4H), 1.62-1.56 (m, 4H), 1.56 (s, 6H), 1.51-1.40 (m, 8H).

EXAMPLE 2684-(((1R)-5-amino-1-((phenylthio)methyl)pentyl)amino)-N-(4-(4,4-dimethylpiperidin-1-yl)benzoyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 261 for Example120D in Example 120E. MS (ESI(+)) m/e 640 (M+H)⁺; ¹H NMR (300 MHz,DMSO-d₆) δ11.96 (s, 1H), 8.55 (d, 1H), 8.31 (d, 1H), 7.85 (dd, 1H), 7.73(d, 2H), 7.26 (d, 2H), 7.21-7.11 (m, 3H), 7.04 (d, 1H), 6.92 (d, 2H),4.09 (m, 2H), 3.37 (m, 4H), 2.72 (t, 4H), 1.76 (m, 2H), 1.52 (m, 2H),1.35 (m, 8H), 1.48 (m, 6H), 0.95 (s, 6H).

EXAMPLE 2694-(((4-(aminomethyl)bicyclo(2.2.2)oct-1-yl)methyl)amino)-N-((4′-fluoro-1,1′-biphenyl-4-yl)carbonyl-3-nitrobenzenesulfonamideEXAMPLE 269A tert-butyl(4-(((4-((((4′-fluoro-1,1′-biphenyl-4-yl)carbonyl)amino)sulfonyl)-2-nitrophenyl)amino)methyl)bicyclo(2.2.2)oct-1-yl)methylcarbamate

The desired product was prepared by substituting Example 162A forExample 1C in Example 1D. MS (ESI(−)) m/e 665 (M−H)⁻.

EXAMPLE 269B4-(((4-(aminomethyl)bicyclo(2.2.2)oct-1-yl)methyl)amino)-N-((4′-fluoro-1,1′-biphenyl-4-yl)carbonyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 269A forExample 120D in Example 120E. MS (ESI(−)) m/e 565 (M−H)⁻; ¹H NMR (300MHz, DMSO-d₆) δ8.67 (d, 1H), 8.50 (t, 1H), 7.99-7.93(m, 3H), 7.82-7.77(mn, 3H), 7.71 (br s, 2H), 7.36-7.27 (m, 3H), 3.26-3.17 (d, 2H), 2.55(q, 2H), 2.52-2.41 (m, 12H).

EXAMPLE 2704-((1,1-dimethyl-2-(phenylthio)ethyl)amino)-N-((4′-fluoro-1,1′-biphenyl-4-yl)carbonyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 267B forExample 1C in Example 1D. MS (ESI(−)) m/e 578 (M−H)⁻; ¹H NMR (300 MHz,DMSO-d6) δ8.47-8.51 (m, 2H), 7.98 (d, 2H), 7.86 (dd, 1H), 7.72-7.78 (m,2H), 7.69 (d, 2H), 7.25-7.35 (m, 5H), 7.06-7.12 (m, 2H), 6.97-7.02 (m,1H), 3.54 (s, 2H), 1.56 (s, 6H).

EXAMPLE 2714-((1,1-dimethyl-2-(phenylthio)ethyl)amino)-N-(4-(4,4-dimethylpiperidin-1-yl)benzoyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 267B andExample 119C for Example 1C and Example 1B, respectively, in Example 1D.MS (ESI(−)) m/e 595 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ11.97 (br s, 1H),8.50-8.47 (m, 2H), 7.85 (dd, 1H), 7.75 (d, 2H), 7.34 (d, 1H), 7.26 (d,2H), 7.08-7.00 (m, 2H), 6.98 (d, 1H), 6.90 (d, 2H), 3.54 (s, 2H),3.36-3.25 (m, 4H), 1.56 (s, 6H), 1.40-1.36 (m, 4H), 0.95 (s, 6H).

EXAMPLE 272 tert-butyl4-(4-((((4-((1,1-dimethyl-2-(phenylthio)ethyl)amino)-3-nitrophenyl)sulfonyl)amino)carbonyl)phenyl)piperazine-1-carboxylate

The desired product was prepared by substituting4-(4-((neopentyloxy)carbonyl)piperazin-1-yl)benzoic acid and Example267B for Example 1B and Example 1C, respectively, in Example 1D. MS(ESI(−)) m/e 668 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ8.49 (t, 1H), 7.84(dd, 1H), 7.79 (d, 2H), 7.33 (d, 1H), 7.26 (d, 2H), 7.08-7.02 (m, 2H),6.98 (d, 1H), 6.92 (d, 2H), 3.45 (s, 2H), 3.45-3.38 (m, 4H), 3.31-3.26(m, 4H), 1.56 (s, 6H), 1.41 (s, 9H).

EXAMPLE 273N-((4′-fluoro-2-methyl-1,1′-biphenyl-4-yl)carbonyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamideEXAMPLE 273A ethyl 4′-fluoro-2-methyl-1,1′-biphenyl-4-carboxylate

The desired product was prepared by substituting 4-bromo-3-methylbenzoicacid ethyl ester and 4-fluorophenylboronic acid for Example 186B andExample 186A, respectively, in Example 186C.

EXAMPLE 273B 4′-fluoro-2-methyl-1,1′-biphenyl-4-carboxylic acid

The desired product was prepared by substituting Example 273A forExample 186C in Example 186D. MS (DCI) m/e 231 (M+H)⁺.

EXAMPLE 273CN-((4′-fluoro-2-methyl-1,1′-biphenyl-4-yl)carbonyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 273B andExample 77B for Example 1B and Example 1C, respectively, in Example 1D.MS (DCI) m/e 566 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ12.43 (br s, 1H),8.78 (t, 1H), 8.64 (d, 1H), 7.94 (dd, 1H), 7.83 (d, 1H), 7.75 (dd, 1H),7.41-7.37 (m, 4H), 7.32-7.27 (m, 5H), 7.22 (d, 1H), 7.18 (m, 1H), 3.68(q, 2H), 3.29 (q, 2H), 2.25 (s, 3H).

EXAMPLE 274 tert-butyl5-(4-((((3-nitro-4-((2-(phenylthio)ethyl)amino)phenyl)sulfonyl)amino)carbonyl)phenyl)-1-benzothiophene-2-carboxylateEXAMPLE 274A methyl 5-bromo-1-benzothiophene-2-carboxylate

A solution of 5-bromo-2-fluorobenzaldehyde (6 g, 29.6 mmol), methylthioglycolate (2.64 mL, 29.6 mmol), and Na₂CO₃ (3.14 g, 29.6 mmol) inmethanol was heated to reflux for 1 hour, poured into brine, andextracted with ethyl acetate (3×). The combined extracts were washedwith brine and filtered through silica gel to provide the desiredproduct. MS (ESI(−)) m/e 270 (M−H)⁻.

EXAMPLE 274B 5-bromo-1-benzothiophene-2-carboxylic acid

The desired product was prepared by substituting Example 274A forExample 1A in Example 1B. MS (ESI(−)) m/e 254 (M−H)⁻.

EXAMPLE 274C tert-butyl 5-bromo-1-benzothiophene-2-carboxylate

A mixture of Example 274B and concentrated H₂SO₄ (0.5 mL) indichloromethane (100 mL) saturated with isobutylene at room temperaturewas stirred for 4 hours and concentrated. The concentrate was purifiedby flash column chromatography on silica gel with 2% ethylacetate/hexanes to provide the desired product.

EXAMPLE 274D tert-butyl5-(4-(methoxycarbonyl)phenyl)-1-benzothiophene-2-carboxylate

The desired product was prepared by substituting Example 274C and4-(methoxycarbonyl)phenylboronic acid for methyl 4-bromobenzoate and4-fluorophenylboronic acid, respectively, in Example 1A.

EXAMPLE 274E 4-(2-(tert-butoxycarbonyl)-1-benzothien-5-yl)benzoic acid

The desired product was prepared by substituting Example 274D forExample 1A in Example 1B. MS (ESI(−)) m/e 353 (M−H)⁻.

EXAMPLE 274F tert-butyl5-(4-((((3-nitro-4-((2-(phenylthio)ethyl)amino)phenyl)sulfonyl)amino)carbonyl)phenyl)-1-benzothiophene-2-carboxylate

The desired product was prepared by substituting Example 274E andExample 77B for Example 1B and Example 1C, respectively, in Example 1D.MS (ESI(−)) m/e 688 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ1.58 (s, 9H),3.29 (t, 2H), 3.65 (dt, 2H), 7.16 (m, 3H), 7.28 (t, 2H), 7.38 (m, 3H),7.41 (m, 1H), 7.81 (d, 1H), 7.88 (d, 2H), 7.92 (dd, 1H), 8.01 (d, 1H),8.14 (d, 1H), 8.61 (dd, 1H), 8.71 (t, 1H).

EXAMPLE 275(3R)-3-((4-((((4′-fluoro-1,1′-biphenyl-4-yl)carbonyl)amino)sulfonyl)-2-nitrophenyl)amino)-4-(phenylthio)butanoicacid

The desired product was prepared by substituting Example 435 for Example122D in Example 122E. MS (ESI(−)) m/e 608 (M−H)⁻; ¹H NMR (300 MHz,methanol-d₄) δ8.71 (d, 1H), 7.99 (d, 2H), 7.92 (dd, 1H), 7.68 (m, 4H),7.26 (m, 2H), 7.21-7.12 (m, 5H), 6.98 (d, 1H), 4.40 (m, 1H), 3.37 (dd,1H), 3.30 (dd, 1H), 2.83 (m, 2H).

EXAMPLE 276(3R)-3-((4-((((2′-methoxy-4′-(3-morpholin-4-ylpropyl)-1,1′-biphenyl-4-yl)carbonyl)amino)sulfonyl)-2-nitrophenyl)amino)-N,N-dimethyl-4-(phenylthio)butanamide

The desired product was prepared by substituting Example 122F andExample 122O for Example 1C and Example 1B, respectively, in Example 1D.MS (ESI(−)) m/e 774 (M−H)⁻; ¹H NMR (500 MHz, methanol-d₄) δ8.72 (d, 1H),8.70 (d, 1H), 7.94 (d, 2H), 7.91 (dd, 1H), 7.45 (d, 2H), 7.35 (d, 1H),7.18 (m, 4H), 6.92 (s, 1H), 6.87 (d, 2H), 3.77 (s, 3H), 3.75 (m, 4H),3.35 (m, 2H), 2.95 (m, 2H), 2.84 (m, 2H), 2.80 (m, 4H), 2.70 (t, 2H),1.94 (m, 2H).

EXAMPLE 277 methylN-(4-((((4′-fluoro-1,1′-biphenyl-4-yl)carbonyl)amino)sulfonyl)-2-nitrophenyl)-S-phenyl-L-cysteinate

The desired product was prepared by substituting Example 133C forExample 1C in Example 1D. MS (ESI(−)) m/e 608 (M−H)⁻; ¹H NMR (300 MHz,DMSO-d₆) δ3.61 (dd, 1H), 3.62 (s, 3H), 3.70 (dd, 1H), 5.10 (m, 1H), 7.11(m, 3H), 7.19 (d, 1H), 7.27 (d, 2H), 7.31 (dd, 2H), 7.75 (m, 4H), 7.92(dd, 1H), 7.97 (d, 2H), 8.55 (d, 1H), 8.80 (d, 1H).

EXAMPLE 278N-(4-(1-(cyclohexylmethyl)-1H-benzimidazol-5-yl)benzoyl)-4-(((1R)-2-hydroxy-1-((phenylthio)methyl)ethyl)amino)-3-nitrobenzenesulfonamideEXAMPLE 278A4-(((1R)-2-((tert-butyl(dimethyl)silyl)oxy)-1-((phenylthio)methyl)ethyl)amino)-3-nitrobenzenesulfonamide

A solution of Example 133B (3 g, 9.63 mmol) in 1:1 dioxane/4M HCl (400mL) was stirred for 90 minutes, poured into saturated Na₂CO₃, andextracted with ethyl acetate (3×). The combined extracts were washedwith brine and concentrated.

The concentrate was purified by flash column chromatography on silicagel with ethyl acetate. A solution of the purified product (1.7 g, 8.04mmol) in THF (100 mL) was treated with 1M LAH in THF (16.1 mL), stirredfor 30 minutes, treated sequentially with water (4 mL), 1M NaOH (4 mL),and water (4 mL), diluted with THF, filtered through a pad of silicagel, and concentrated.

A solution of the concentrate (1.35 g, 7.37 mmol),tert-butyldimethylsilyl triflate (1.86 mL, 8.10 mmol), and 2,6-lutidine(0.943 mL, 8.10 mmol) in dichloromethane (50 mL) at 0° C. was stirredfor 30 minutes, added to a solution of Example 122C (1.76 g, 8 mmol) inDMF (50 mL) and diisopropylethylamine (15 mL), heated to 50° C., stirredfor 18 hours, poured into water, and extracted with ethyl acetate (333). The combined extracts were washed with water and brine, dried(Na₂SO₄), filtered, and concentrated. The concentrate was purified byflash column chromatography on silica gel with 50% ethyl acetate/hexanesto provide the desired product. MS (ESI(−)) m/e 496 (M−H)⁻.

EXAMPLE 278BN-(4-(1-(cyclohexylmethyl)-1H-benzimidazol-5-yl)benzoyl)-4-(((1R)-2-hydroxy-1-((phenylthio)methyl)ethyl)amino)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 286A andExample 278B for Example 1B and Example 1C, respectively, in Example 1D.The product was dissolved in TFA (5 mL), stirred for 2 hours,concentrated, dissolved in toluene, and concentrated again to providethe desired product. MS (ESI(−)) m/e 698 (M−H)⁻; ¹H NMR (300 MHz,DMSO-d₆) δ0.90-1.35 (m, 6H), 1.58 (m, 5H), 3.02 (m, 3H), 3.18 (m, 2H),3.54 (dd, 1H), 3.68 (dd, 1H), 4.19 (m, 1H), 7.16 (m, 2H), 7.21 (d, 2H),7.30 (d, 2H), 7.62 (m, 1H), 7.73 (m, 2H), 7.87 (m, 4H), 7.98 (d, 1H),8.04 (s, 1H), 8.59 (d, 1H), 8.61 (d, 1H).

EXAMPLE 279(3R)-3-((4-((((4′-fluoro-1,1′-biphenyl-4-yl)carbonyl)amino)sulfonyl)-2-nitrophenyl)amino)-N-(3-morpholin-4-ylpropyl)-4-(phenylthio)butanamide

The desired product was prepared by substituting Example 275 and4-(3-aminopropyl)morpholine for Example 1B and Example 1C, respectively,in Example 1D. MS (ESI(−)) m/e 734 (M−H)⁻; ¹H NMR (500 MHz, methanol-d₄)δ8.65 (d, 1H), 8.50 (d, 1H), 8.13 (d, 2H), 7.89 (dd, 1H), 7.64 (m, 2H),7.58 (d, 2H), 7.29 (d, 2H), 7.14 (m, 5H), 6.89 (d, 1H), 4.40 (m, 1H),3.62 (t, 4H), 3.32 (dd, 1H), 3.21 (m, 2H), 3.09 (m, 1H), 2.68 (m, 2H),2.37 (m, 4H), 2.29 (t, 2H), 1.58 (m, 2H).

EXAMPLE 280N-((4′-fluoro-1,1′-biphenyl-4-yl)carbonyl)-4-(((1R)-3-hydroxy-1-((phenylthio)methyl)propyl)amino)-3-nitrobenzenesulfonamideEXAMPLE 280A4-(((1R)-3-hydroxy-1-((phenylthio)methyl)propyl)amino)-3-nitrobenzenesulfonamide

A mixture of Example 122E (206 mg, 0.50 mmol) and 1M borane in THF (20mL) was stirred for 16 hours, treated sequentially with methanol (5.0mL) and 1N HCl (2.0 mL), diluted with ethyl acetate (50 mL), washed withwater (2 mL) and brine (10 mL), dried (MgSO₄), filtered, andconcentrated The concentrate was purified by flash column chromatographyon silica gel with 20-50% ethyl acetate/dichloromethane to provide thedesired product. MS (ESI(+)) m/e 398 (M+H)⁺.

EXAMPLE 280BN-((4′-fluoro-1,1′-biphenyl-4-yl)carbonyl)-4-(((1R)-3-hydroxy-1-((phenylthio)methyl)propyl)amino)-3-nitrobenzenesulfonamide

A room temperature solution of Example 280A (150 mg, 0.38 mmol), Example1B (180 mg, 0.83 mmol), EDCI (193 mg, 1.0 mmol), and DMAP (25 mg, 0.20mmol) in dichloromethane (10 mL) was stirred for 16 hours, diluted withethyl acetate (100 mL), washed sequentially with 1M HCl (20 mL), water(30 mL) and brine (20 mL), dried (MgSO₄), filtered, and concentrated.

The concentrate was dissolved in THF (5 mL), treated with 1M LiOH (1.0mL), stirred for 3 hours, diluted with ethyl acetate (60 mL), washedsequentially with 1M HCl (10 mL), water (20 mL), and brine (10 mL),dried (MgSO₄), filtered, and concentrated. The concentrate was purifiedby flash column chromatography on silica gel with 30-100% ethylacetate/dichloromethane to provide the desired product. MS (ESI(−)) m/e594 (M−H)⁻; ¹H NMR (500 MHz, methanol-d₄) δ8.72 (d, 1H), 7.92 (m, 3H),7.70 (m, 4H), 7.26 (m, 2H), 7.18 (tt, 2H), 7.11 (m, 3H), 7.00 (d, 1H),4.25 (m, 1H), 3.68 (m, 2H), 3.39 (d, 1H), 3.21 (m, 3H), 2.08 (m, 1H),1,97 (m, 1H).

EXAMPLE 2814-(((1R)-2-hydroxy-1-((phenylthio)methyl)ethyl)amino)-N-((2′-methoxy-4′-(3-morpholin-4-yl-3-oxopropyl)-1,1′-biphenyl-4-yl)carbonyl)-3-nitrobenzenesulfonamideEXAMPLE 281A2′-methoxy-4′-(3-morpholin-4-yl-3-oxopropyl)-1,1′-biphenyl-4-carboxylicacid

The desired product was prepared by substituting Example 122M forExample 1A in Example 1B.

EXAMPLE 281B4-(((1R)-2-hydroxy-1-((phenylthio)methyl)ethyl)amino)-N-((2′-methoxy-4′-(3-morpholin-4-yl-3-oxopropyl)-1,1′-biphenyl-4-yl)carbonyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 281A andExample 278A for Example 1B and Example 1C, respectively, in Example 1D.The product was dissoved in TFA (5 mL), stirred for 2 hours,concentrated, dissolved in toluene, and concentrated again to providethe desired product. MS (ESI(−)) m/e 733 (M−H)⁻; ¹H NMR (300 MHz,DMSO-d₆) δ2.66 (t, 2H), 2.85 (t, 2H), 3.28 (m, 2H), 3.43 (m, 4H), 3.52(m, 4H), 3.62 (m, 1H), 3.71 (m, 1H), 3.76 (s, 3H), 3.96 (m, 1H),5.41(dd, 1H), 6.90 (d, 2H), 6.99 (s, 1H), 7.20 (dd, 2H), 7.28 (dd, 2H),7.35 (d, 2H), 7.43 (d, 2H), 7.81 (dd, 1H), 7.89 (d, 2H), 8.47 (d, 1),8.51 (t, 1H).

EXAMPLE 282N-(4-(8-azaspiro(4.5)dec-8-yl)benzoyl)-4-(((1R)-2-hydroxy-1-((phenylthio)methyl)ethyl)amino)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 257C andExample 278A for Example 1B and Example 1C, respectively, in Example 1D.The product was dissoved in TFA (5 mL), stirred for 2 hours,concentrated, dissolved in toluene, and concentrated again to providethe desired product. MS (ESI(−)) m/e 623 (M−H)⁻; ¹H NMR (300 MHz,DMSO-d₆) δ1.45 (m, 8H), 1.59 (m, 4H), 3.27 (m, 4H), 3.62 (dd, 1H), 3.69(dd, 1H), 4.04 (m, 1H), 5.21 (t, 1H), 6.84 (d, 1H), 6.92 (d, 2H), 7.08(d, 1H), 7.18 (d, 1H), 7.21 (m, 2H), 7.31 (d, 2H), 7.71 (d, 1H), 7.82(dd, 1H), 8.56 (d, 1H), 8.57 (t, 1H).

EXAMPLE 2834-(((1R)-5-amino-1-((phenylthio)methyl)pentyl)amino)-N-((4′-(3-hydroxypropyl)-2′-methoxy-1,1′-biphenyl-4-yl)carbonyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 451B forExample 122N in Example 194. MS (ESI(−)) m/e 691 (M−H)⁻; ¹H NMR (300MHz, DMSO-d₆) δ8.55 (d, 1H), 8.35 (br d, 1H), 7.90 (d, 2H), 7.85 (dd,1H), 7.58 (d, 2H), 7.25-7.12 (m, 7H), 7.00 (d, 1H), 6.89 (dd, 1H), 4.10(m, 1H), 3.75 (s, 3H), 3.72 (s, 2H), 3.35 (m, 2H), 2.70-2.605 (m, 6H),1.75 (m, 4H), 1.50 (m, 2H), 1.40 (m, 2H).

EXAMPLE 2844-(((1R)-5-amino-1-((phenylthio)methyl)pentyl)amino)-N-(4-(5-fluoroquinolin-8-yl)benzoyl)-3-nitrobenzenesulfonamideEXAMPLE 284A methyl 4-(5-fluoroquinolin-8-yl)benzoate

The desired product was prepared by substituting Example 389A forExample 5A in Example 5B.

EXAMPLE 284B 4-(5-fluoroquinolin-8-yl)benzoic acid

The desired product was prepared by substituting Example 284A forExample 1A in Example 1B.

EXAMPLE 284C4-(((1R)-5-amino-1-((phenylthio)methyl)pentyl)amino)-N-(4-(5-fluoroquinolin-8-yl)benzoyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 284B forExample 122N in Example 194. MS (ESI(−)) m/e 674 (M−H)⁻; ¹H NMR (300MHz, DMSO-d₆) δ9.00 (dd, 1H), 8.90 (br d, 1H), 8.60 (d, 1H), 8.58 (dd,1H), 7.90 (d, 2H), 7.85 (m, 2H), 7.75 (d, 2H), 7.70 (m, 1H), 7.55 (m,1H), 7.25-7.12 (m, 6H), 4.15 (m, 1H), 3.45 (m, 2H), 2.75 (m, 2H), 2.80(s, 3H), 1.80 (m, 2H), 1.55 (m, 2H), 1.40 (m, 2H).

EXAMPLE 285N-(4-(6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamideEXAMPLE 285A ethyl 4-(6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)benzoate

The desired product was prepared by subtituting6-methoxy-1,2,3,4-tetrahydroisoquinoline (prepared according to theprocedure described in U.S. Pat. No. 1,845,403) for1,4-dioxa-8-azasprio(4,5)decane in Example 158A. MS (DCI) m/e 312(M+H)⁺.

EXAMPLE 285B 4-(6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)benzoic acid

The desired product was prepared by subtituting Example 285A for Example119B in Example 119C. MS (DCI) m/e 283 (M+H)⁺.

EXAMPLE 285CN-(4-(6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 285B andExample 77B for Example 1B and Example 1C, respectively, in Example 1D.MS (ESI(−)) m/e 617 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ11.98 (s, 1H),8.71 (t, 1H), 8.56 (d, 1H), 7.90 (dd, 1H), 7.77 (d, 2H), 7.37 (d, 2H),7.27 (t, 2H), 7.16 (m, 3H) 6.93 (d, 2H), 6.78 (m, 2H), 4.43 (s, 2H),3.72 (s, 3H), 3.65 (m, 2H), 3.58 (t, 2H), 3.28 (m, 2H), 2.88 (t, 2H).

EXAMPLE 286 tert-butyl(5R)-5-((4-(((4-(1-(cyclohexylmethyl)-1H-benzimidazol-5-yl)benzoyl)amino)sulfonyl)-2-nitrophenol)amino)-6-(phenylthio)hexylcarbamateEXAMPLE 286A 4-bromo-N¹-(cyclohexylmethyl)benzene-1,2-diamine

The desired product was prepared by substituting cyclohexylmethylaminefor butylamine in Examples 166A and 166B.

EXAMPLE 286B 4-(1-(cyclohexylmethyl)-1H-benzimidazol-5-yl)benzoic acid

The desired product was prepared by substituting Example 286A forExample 170A in Examples 170B and 170C.

EXAMPLE 286Ctert-butyl(5R)-5-((4-(((4-(1-(cyclohexylmethyl)-1H-benzimidazol-5-yl)benzoyl)amino)sulfonyl)-2-nitrophenyl)amino)-6-(phenylthio)hexylcarbamate

The desired product was prepared by substituting Example 286B andExample 124C for Example 1B and Example 1C, respectively, in Example 1D.MS (ESI) m/e 839, 841 (M−H)⁻, (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆)δ0.95-1.20 (m, 7H), 1.32 (m, 11H), 1.48-1.76 (m, 7H), 1.85 (m, 1H), 2.86(m, 2H), 3.98 (t, 2H), 4.02 (m, 1H), 4.12 (d, 2H), 6.72 (t, 1H), 6.98(d, 1H), 7.14 (tt, 1H), 7.21 (t, 2H), 7.29 (dd, 2H), 7.59 (dd, 1H), 7.68(d, 3H), 7.84 (dd, 1H), 7.95 (d, 1H), 7.97 (d, 2H), 8.19 (d, 1H), 8.23(t, 1H), 8.49 (d, 1H).

EXAMPLE 2874-(((1R)-5-amino-1-((phenylthio)methyl)pentyl)amino)-N-(4-(8-azaspiro(4.5)dec-8-yl)benzoyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 257D forExample 120D in Example 120E. MS (ESI(+)) m/e 766 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ8.52 (d, 1H), 8.31 (d, 1H), 8.85 (dd, 1H), 7.72 (d, 2H),7.68 (s, 2H), 7.24 (t, 2H), 7.12 (m, 2H), 6.91 (d, 2H), 4.10 (m, 1H),3.42 (m, 4H), 3.31 (m, 6H), 2.71 (mn, 2H), 1.77 (m, 2H), 1.59 (m, 4H),1.52 (m, 2H), 1.45 (m, 6H).

EXAMPLE 288(3R)-3-((4-(((4-(5-fluoroquinolin-8-yl)benzoyl)amino)sulfonyl)-2-nitrophenyl)amino)-N,N-dimethyl-4-(phenylthio)butanamide

The desired product was prepared by substituting Example 284B forExample 126A in Example 126B. MS (ESI(−)) m/e 686 (M−H)⁻; ¹H NMR (300MHz, DMSO-d₆) δ9.00 (dd, 1H), 8.90 (br d, 1H), 8.60 (d, 1H), 8.58 (dd,1H), 7.90 (d, 2H), 7.85 (m, 2H), 7.75 (d, 2H), 7.70 (m, 1H), 7.55 (m,1H), 7.25-7.12 (m, 6H), 4.45 (m, 1H), 3.45 (m, 2H), 2.90 (s, 3H), 2.80(s, 3H), 3.00-2.80 (m, 2H).

EXAMPLE 289(3R)-3-((4-((((2′-methoxy-4′-(3-morpholin-4-yl-3-oxopropyl)-1,1′-biphenyl-4-yl)carbonyl)amino)sulfonyl)-2-nitrophenyl)amino)-N,N-dimethyl-4-(phenylthio)butanamide

The desired product was prepared by substituting Example 122M forExample 126A in Example 126B. MS (ESI(−)) m/e 788 (M−H)⁻; ¹H NMR (300MHz, DMSO-d₆) δ8.89 (br d, 1H), 8.57 (d, 1H), 7.90 (d, 2H), 7.85 (dd,1H), 7.78 (br d, 1H), 7.58 (d, 2H), 7.30-7.12 (m, 7H), 7.00 (d, 1H),6.89 (dd, 1H), 4.45 (m, 1H), 3.75 (s, 3H), 3.55 (m, 4H), 3.45 (m, 6H),2.90 (s, 3H), 2.79 (s, 3H), 3.10-2.70 (m, 4H), 2.65 (t, 2H).

EXAMPLE 2904-(((1R)-3-hydroxy-1-((phenylthio)methyl)propyl)amino)-N-((2′-methoxy-4′-(3-morpholin-4-ylpropyl)-1,1′-biphenyl-4-yl)carbonyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 122O forExample 1B in Example 280B. MS (ESI(−)) m/e 774 (M−H)⁻; ¹H NMR (500 MHz,methanol-d₄) δ8.72 (d, 1H), 8.69 (d, 1H), 7.95 (d, 2H), 7.90 (dd, 1H),7.45 (d, 2H), 7.34 (d, 2H), 7.22-7.10 (m, 5H), 6.92 (s, 1H), 6.85 (d,1H), 4.40 (m, 1H), 3.77 (s, 3H), 3.80-3.72 (m, 4H), 3.36 (m, 3H), 2.95(m, 2H), 2.85 (m, 2H), 2.79 (m, 3H), 2.70 (m, 4H), 1.95 (m, 3H).

EXAMPLE 2914-((2-((4-chlorophenyl)thio)ethyl)amino)-N-((4′-fluoro-1′-biphenyl-4-yl)carbonyl)-3-nitrobenzenesulfonamideEXAMPLE 291A 2-((4-chlorophenyl)thio)ethanamine

A solution of sodium metal (22.5 mg, 0.98 mmol) in ethanol (2.0 mL) wastreated with 2-bromoethylamine hydrobromide (100.0 mg, 0.49 mmol) and4-chlorobenzenethiol (71.0 mg, 0.49 mmol), heated to 75° C. for 18hours, and concentrated. The concentrate was partitioned between water(2.0 mL) and diethyl ether (5.0 mL) and the organic phase was dried(MgSO₄), filtered, and concentrated to provide the desired product. MS(DCI) m/e 188 (M+H)⁺.

EXAMPLE 291B4-((2-((4-chlorophenyl)thio)ethyl)amino)-N-((4′-fluoro-1,1′-biphenyl-4-yl)carbonyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 291A for2,2-dimethylcyclopentylamine in Example 1E. MS (DCI) m/e 603 (M+NH₄)⁺;¹H NMR (300 MHz, DMSO-d₆) δ12.49 (br s, 1H), 8.76 (t, 1H), 8.64 (d, 1H),7.97-7.95 (m, 3H), 7.80-7.77 (m, 4H), 7.39-7.38 (m, 2H), 7.34-7.30 (m,4H), 7.24 (d, 1H), 3.68 (q, 2H), 3.30 (q, 2H).

EXAMPLE 2924-(((1R)-5-amino-1-((phenylthio)methyl)pentyl)amino)-3-nitro-N-(4-(5-(trifluoromethyl)pyridin-2-yl)benzoyl)benzenesulfonamide

The desired product was prepared by substituting Example 124C andExample 253B for Example 124E and Example 257C, respectively, in Example124F. MS (ESI) m/e 674, 672 (M+H)⁺, (M−H)⁻; ¹H NMR (500 MHz, DMSO-d₆)δ9.09 (dd, 1H), 8.59 (d, 1H), 8.35-8.29 (m, 5H), 8.06 (d, 2H), 7.90 (dd,1H), 7.25 (dt, 2H), 7.15 (td, 2H), 7.10 (tt, 1H), 4.12 (m, 1H), 3.37 (t,2H), 2.73 (m, 2H), 1.77 (q, 2H), 1.54 (m, 2H), 1.39 (m, 2H).

EXAMPLE 293N-(4-(5-chloropyridin-2-yl)benzoyl)-4-(((1R)-5-(dimethylamino)-1-((phenylthio)methyl)pentyl)amino)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 254B forExample 257C in Example 124F. MS (ESI) m/e 668, 666 (M+H)⁺, (M−H)⁻; ¹HNMR (500 MHz, DMSO-d₆) δ10.02 (s, 1H), 8.75 (dd, 1H), 8.58 (d, 1H), 8.33(d, 1H), 8.21 (d, 2H), 8.12 (dd, 1H), 8.06 (dd, 1H), 8.01 (d, 2H), 7.90(dd, 1H), 7.25 (dt, 2H), 7.15 (td, 2H), 7.10 (tt, 1H), 4.12 (m, 1H),3.36 (d, 2H), 2.95 (m, 2H), 2.69 (s, 3H), 2.69 (s, 3H), 1.78 (q, 2H),1.63 (m, 2H), 1.36 (m, 2H).

EXAMPLE 2944-(((1R)-5-(dimethylamino)-1-((phenylthio)methyl)pentyl)amino)-3-nitro-N-(4-quinolin-8-ylbenzoyl)benzenesulfonamideEXAMPLE 294A methyl 4-quinolin-8-ylbenzoate

The desired product was prepared by substituting 8-bromoquinoline for5-bromo-2-methoxypyridine in Example 252D. MS (ESI) m/e 250, 248 (M+H)⁺,(M−H)⁻.

EXAMPLE 294B 4-quinolin-8-ylbenzoic acid

The desired product was prepared by substituting Example 294A forExample 252F in Example 252G.

EXAMPLE 294C4-((((1R)-5-(dimethylamino)-1-((phenylthio)methyl)pentyl)amino)-3-nitro-N-(4-quinolin-8-ylbenzoyl)benzenesulfonamide

The desired product was prepared by substituting Example 294B forExample 257C in Example 124F. MS (ESI) m/e 684, 682 (M+H)⁺, (M−H)⁻; ¹HNMR (500 MHz, DMSO-d₆) δ10.34 (s, 1H), 8.94 (dd, 1H), 8.59 (d, 1H), 8.55(dd, 1H), 8.33 (d, 1H), 8.19 (dd, 1H), 8.07 (d, 2H), 8.00 (d, 1H), 7.92(dd, 1H), 7.86 (dd, 1H), 7.82 (d, 2H), 7.80-7.72 (m, 2H), 7.65 (m, 1H),7.31-7.10 (m, 5H), 4.16 (m, 1H), 3.37 (m, 2H), 2.95 (m, 2H), 2.69 (s,3H), 1.78 (m, 2H), 1.64 (m, 2H), 1.38 (m, 2H).

EXAMPLE 2954-(((1R)-5-(dimethylamino)-1-((phenylthio)methyl)pentyl)amino)-N-((4′-(3-hydroxypropyl)-2′-methoxy-1,1′-biphenyl-4-yl)carbonyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 451B forExample 257C in Example 124F. The crude product was dissolved in THF,treated with TBAF (50 mg), stirred for 3 hours, and concentrated. Theconcentrate was purified by HPLC (using a C-18 column and a solventsystem increasing in gradient from 10-95% acetonitrile/water containing0.1% TFA) to provide the desired product which was converted to thehydrochloride salt by dissolving the product in methanol and 2M HCl indiethyl ether then concentrating. MS (ESI) m/e 721, 719 (M+H)⁺, (M−H)⁻;¹H NMR (500 MHz, DMSO-d₆) δ8.57 (d, 1H), 8.32 (d, 1H), 7.89 (d, 2H),7.59 (d, 2H), 7.27-7.10 (m, 8H), 6.97 (d, 1H), 6.87 (d, H), 4.12 (m,1H), 3.76 (s, 3H), 3.44 (t, 2H), 3.36 (m, 2H), 2.95 (m 2H), 2.69 (s,3H), 2.67 (s, 3H), 2.65 (m, 2H), 1.77 (m, 2H), 1.64 (m, 2H), 1.36 (m,2H).

EXAMPLE 2964-(((1R)-5-(dimethylamino)-1-((phenylthio)methyl)pentyl)amino)-N-(4-(4-methoxy-2-oxopyridin-1(2H)-yl)benzoyl)-3-nitrobenzenesulfonamideEXAMPLE 296A methyl 4-(4-hydroxy-2-oxopyridin-1(2H)-yl)benzoate

A mixture of methyl 4-iodobenzoate (0.421 g, 1.6 mmol),2,4-dihydroxypyridine (0.174 g, 1.34 mmol), CuI (25 mg, 0.134 mmol) andK₂CO₃ (200 mg) in DMF (2 mL) was heated to 150° C. in a sealed vial for4 hours, diluted with ethyl acetate (100 mL), washed with water (30 mL)and brine (30 mL), dried (Na₂SO₄), filtered, and concentrated. Theconcentrate was purified by flash column chromatography on silica gelwith 2:1 hexanes/ethyl acetate to provide the desired product. MS (APCI)m/e 246 (M+H)⁺.

EXAMPLE 296B methyl 4-(4-methoxy-2-oxopyridin-1(2H)-yl)benzoate

A solution of Example 296A (2.3 g, 10 mmol) in acetone (300 mL) wastreated with iodomethane (5 mL) and K₂CO₃ (15 g), heated to reflux for18 hours, and filtered. The filtrate was concentrated and he concentratepurified by flash column chromatography on silical gel with 4:1hexanes/ethyl acetate to provide the desired product. MS (ESI) m/e 260(M+H)⁺.

EXAMPLE 296C 4-(4-methoxy-2-oxopyridin-1(2H)-yl)benzoic acid

The desired product was prepared by substituting Example 296B forExample 252F in Example 252G. MS (ESI) m/e 246, 244 (M+H)⁺, (M−H)⁻.

EXAMPLE 296D4-(((1R)-5-(dimethylamino)-1-((phenylthio)methyl)pentyl)amino)-N-(4-(4-methoxy-2-oxopyridin-1(2H)-yl)benzoyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 296C forExample 257C in Example 124F. MS (ESI) m/e 680, 678 (M+H)⁺, (M−H)⁻; ¹HNMR (500 MHz, DMSO-d₆) δ8.57 (d, 1H), 8.33 (d, 1H), 8.05 (d, 1H), 7.99(d, 2H), 7.89 (dd, 1H), 7.57 (d, 1H), 7.52 (d, 2H), 7.10-7.33 (m, 5H),6.07 (dd, 1H), 5.88 (d, 1H), 4.12 (m, 1H), 3.89 (s, 3H), 3.36 (m, 2H),2.95 (m, 2H), 2.69 (s, 3H), 2.67 (s, 3H), 1.77 (m, 2H), 1.64 (m, 2H),1.34 (m, 2H).

EXAMPLE 2974-(((1R)-5-amino-1-((phenylthio)methyl)pentyl)amino)-N-(4-(4-methoxy-2-oxopyridin-1(2H)-yl)benzoyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 124C andExample 296C for Example 124E and Example 257C, respectively, in Example124F. MS (ESI) m/e 652, 650 (M+H)⁺, (M−H)⁻; ¹H NMR (500 MHz, DMSO-d₆)δ8.57 (d, 1H), 8.33 (d, 1H), 8.05 (d, 1H), 7.99 (d, 2H), 7.89 (dd, 1H),7.57 (d, 1H), 7.52 (d, 2H), 7.25 (dt, 2H), 7.15 (td, 2H), 7.10 (tt, 1H),6.08 (dd, 1H), 5.88 (d, 1H), 4.12 (m, 1H), 3.89 (s, 3H), 3.36 (t, 2H),2.73 (m, 2H), 1.76 (q, 2H), 1.56 (m, 2H), 1.39 (m, 2H).

EXAMPLE 2984-(((1R)-5-amino-1-((phenylthio)methyl)pentyl)amino)-N-((6-(4-fluorophenyl)pyridin-3-yl)carbonyl)-3-nitrobenzenesulfonamideEXAMPLE 298A methyl 6-(4-fluorophenyl)nicotinate

The desired product was prepared by substituting methyl6-chloronicotinate and 4-fluorobenzeneboronic acid for5-bromo-2-methoxypyridine and 4-methylcarboxybenzeneboronic acid,respectively, in Example 252D. MS (APCI) m/e 232 (M+H)⁺.

EXAMPLE 298B 6-(4-fluorophenyl)nicotinic acid

The desired product was prepared by substituting Example 298A forExample 252F in Example 252G. MS (ESI) m/e 218, 216 (M+H)⁺, 216(M−H)⁻.

EXAMPLE 298C4-(((1R)-5-amino-1-((phenylthio)methyl)pentyl)amino)-N-((6-(4-fluorophenyl)pyridin-3-yl)carbonyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 124C andExample 298B for Example 124E and Example 257C, respectively, in Example124F. MS (ESI) m/e 624, 622, (M+H)⁺, (M−H)⁻; ¹H NMR(500 MHz, DMSO-d₆)δ9.10(d, 1H), 8.59 (d, 1H), 8.36-8.33 (m, 2H), 8.24-8.21 (m, 2H),8.16-8.12 (m, 1H), 7.91 (dd, 1H), 7.39-7.31 (m, 2H), 7.25 (dt, 2H), 7.15(td, 2H), 7.10 (tt, 1H), 6.94 (d, 1H), 4.12 (m, 1H), 3.37 (t, 2H), 3.37(t, 2H), 2.73 (m, 2H), 1.76 (q, 2H), 1.56 (m, 2H), 1.39 (m, 2H).

EXAMPLE 2994-(((1R)-5-amino-1-((phenylthio)methyl)pentyl)amino)-N-(4-(6-methoxypyridin-3-yl)benzoyl)-3-nitrobenzenesulfonamideEXAMPLE 299A 4-(6-methoxypyridin-3-yl)benzoic acid

The desired product was prepared by substituting Example 252D forExample 252F in Example 252G. MS (ESI) m/e 230(M+H)⁺, m/e 228 (M−H)⁻.

EXAMPLE 299B4-(((1R)-5-amino-1-((phenylthio)methyl)pentyl)amino)-N-(4-(6-methoxypyridin-3-yl)benzoyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 124C andExample 299A for Example 124E and Example 257C, respectively, in Example124F. MS (ESI) m/e 636, 634 (M+H)⁺, (M−H)⁻; ¹H NMR (500 MHz, DMSO-d₆)δ8.58 (d, 1H), 8.33 (d, 1H), 8.06 (dd, 1H), 8.09 (dd, 1H), 8.02 (d, 2H),7.98 (d, 1H), 7.91 (dd, 1H), 7.83 (d, 2H), 7.81 (s, 1H), 7.25 (dt, 2H),7.15 (td, 2H), 7.10 (tt, 1H), 6.94 (d, 1H), 4.12 (m, 1H), 3.91 (s, 3H),3.36 (t, 2H), 2.73 (m, 2H), 1.76 (q, 2H), 1.56 (m, 2H), 1.39 (m, 2H).

EXAMPLE 3002-(4′-((((4-(((1R)-5-(dimethylamino)-1-((phenylthio)methyl)pentyl)amino)-3-nitrophenyl)sulfonyl)amino)carbonyl)-2-methoxy-1,1′-biphenyl-4-yl)-N,N-dimethylacetamide

The desired product was prepared by substituting Example 441A andExample 122F for Example 5C and Example 3A, respectively, in Example 5D.MS (ESI) m/e 748, 746 (M+H)⁺, (M−H)⁻; ¹H NMR (500 MHz, DMSO-d₆) δ9.95(s, 1H), 8.57 (d, 1H), 8.34 (d, 1H), 7.98 (d, 2H), 7.90 (d, 1H), 7.62(d, 2H), 7.60 (d, 1H), 7.28-7.24 (m, 3H), 7.18-7.08 (m, 3H), 7.01 (dd,1H), 6.90 (dd, 2H), 4.12 (m, 1H),3.87 (s, 3H), 3.76 (s, 3H), 3.73 (t,2H), 3.36 (m, 2H), 3.03 (s, 3H), 2.85 (s, 3H), 2.68 (d, 2H), 1.77 (q,2H), 1.64 (m, 2H), 1.36 (m, 2H).

EXAMPLE 3014-(((1R)-5-(dimethylamino)-1-((phenylthio)methyl)pentyl)amino)-N-((2′-methoxy-4′-(3-morpholin-4-yl-3-oxopropyl)-1,1′-biphenyl-4-yl)carbonyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 122O forExample 257C in Example 124F. MS (ESI) m/e 804, 802 (M+H)⁺, (M−H)⁻; ¹HNMR (500 MHz, DMSO-d⁶) δ10.02 (s, 1H), 8.57 (d, 1H), 8.34 (d, 1H), 7.97(d, 1H), 7.90 (d, 2H), 7.60 (d, 1H), 7.58 (d, 2H), 7.27-7.10 (m, 6H),7.03 (dd, 1H), 6.94 (dd, 1H), 4.12 (m, 1H), 3.75 (s, 3H), 3.51 (m, 4H),3.44 (m, 4H), 3.36 (m, 2H), 2.95 (m, 2H), 2.86 (m, 2H), 2.69 (s, 3H),2.67 (s, 3H), 1.77 (q, 2H), 1.64 (m, 2H), 1.36 (m, 2H).

EXAMPLE 3024-(((1R)-5-amino-1-((phenylthio)methyl)pentyl)amino)-N-(4-(6-chloropyridin-3-yl)benzoyl)-3-nitrobenzenesulfonamide

The desired was prepared by substituting Example 124C and Example 252Gfor Example 124E and Example 257C, respectively, in Example 124F. MS(ESI) m/e 638 (M−H)⁻; ¹H NMR (500 MHz, DMSO-d₆) δ8.81 (dd, 1H), 8.58 (d,1H), 8.34 (d, 1H), 8.23 (dd, 1H), 8.02 (d, 2H), 7.90 (d, 2H), 7.89 (dd,1H), 7.64 (d, 1H), 7.25 (dt, 2H), 7.15 (td, 2H), 7.10 (tt, 1H), 4.12 (m,1H), 3.36 (t, 2H), 2.73 (m, 2H), 1.76 (q, 2H), 1.56 (m, 2H), 1.39 (m,2H).

EXAMPLE 3034-(((1R)-5-amino-1-((phenylthio)methyl)pentyl)amino)-N-(4-(5-chloropyridin-2-yl)benzoyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 124C andExample 254B for Example 124E and Example 257C, respectively, in Example124F. MS (ESI) m/e 640, 638 (M+H)⁺, (M−H)⁻; ¹H NMR (500 MHz, DMSO-d₆)δ8.74 (dd, 1H), 8.58 (d, 1H), 8.34 (d, 1H), 8.20 (d, 2H), 8.12 (d, 1H),8.06 (dd, 1H), 8.01 (d, 2H), 7.90 (dd, 1H), 7.25 (dt, 2H), 7.15 (td,2H), 7.10 (tt, 1H), 4.12 (m, 1H), 3.36 (t, 2H), 2.73 (m, 2H), 1.76 (q,2H), 1.56 (m, 2H), 1.39 (m, 2H).

EXAMPLE 3044-(((1R)-5-(dimethylamino)-1-((phenylthio)methyl)pentyl)amino)-N-(4-(5-fluoroquinolin-8-yl)benzoyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 284B forExample 257C in Example 124F. MS (ESI) m/e 702, 700 (M+H)⁺, (M−H)⁻; ¹HNMR (500 MHz, DMSO-d₆) δ8.98 (dd, 1H), 8.59 (d, 1H), 8.87 (dd, 1H), 8.06(d, 1H), 7.99 (d, 2H), 7.92 (dd, 1H), 7.84 (d, 1H), 7.80 (d, 1H), 7.77(d, 2H), 7.70 (q, 1H), 7.67 (t, 1H), 7.29-7.10 (m, 5H), 4.12 (m, 1H),3.36 (m, 2H), 2.95 (m, 2H), 2.69 (s, 3H), 2.67 (s, 3H), 1.77 (q, 2H),1.64 (m, 2H), 1.36 (m, 2H).

EXAMPLE 3054-(((1R)-5-(dimethylamino)-1-((phenylthio)methyl)pentyl)amino)-3-nitro-N-(4-(5-(trifluoromethyl)pyridin-2-yl)benzoyl)benzenesulfonamide

The desired product was prepared by substituting Example 253B forExample 257C in Example 124F. MS (ESI) m/e 702, 700 (M+H)⁺, (M−H)⁻; ¹HNMR (500 MHz, DMSO-d₆) δ9.08 (d, 1H), 8.58 (d, 1H), 8.34-8.30 (m, 2H),8.30 (d, 2H), 8.10 (d, 1H), 8.06 (d, 2H), 7.92 (dd, 1H), 7.27-7.10 (m,5H), 4.12 (m, 1H), 3.36 (m, 2H), 2.95 (m, 2H), 2.69 (s, 3H), 2.67 (s,3H), 1.77 (q, 2H), 1.64 (m, 2H), 1.36 (m, 2H).

EXAMPLE 3064-(((1R)-5-amino-1-((phenylthio)methyl)pentyl)amino)-N-(4-(5-chloro-2-oxopyridin-1(2H)-yl)benzoyl)-3-nitrobenzenesulfonamideEXAMPLE 306A methyl 4-(5-chloro-2-oxopyridin-1(2H)-yl)benzoate

The desired product was prepared by substituting5-chloro-2-hydroxypyridine for 2,4-dihydroxypyridine in Example 296A. MS(ESI) m/e 264 (M+H)⁺.

EXAMPLE 306B 4-(5-chloro-2-oxopyridin-1(2H)-yl) benzoic acid

The desired product was prepared by substituting Example 306A forExample 252F in Example 252G. MS (ESI) m/e 250, 248 (M+H)⁺, (M−H)⁻.

EXAMPLE 306C4-(((1R)-5-amino-1-((phenylthio)methylpentyl)amino)-N-(4-(5-chloro-2-oxopyridin-1(2H)-yl)benzoyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 124C andExample 306B for Example 124E and Example 257C, respectively, in Example124F. MS (ESI) m/e 656, 654 (M+H)⁺, (M−H)⁻; ¹H NMR (500 MHz, DMSO-d₆)δ8.58 (d, 1H), 8.34 (d, 1H), 8.01 (d, 2H), 7.95 (d, 1H), 7.89 (dd, 1H),7.60 (d, 2H), 7.58 (dd, 1H), 7.26 (dt, 2H), 7.14 (td, 2H), 7.10 (tt,1H), 6.54 (d, 1H), 4.12 (m, 1H), 3.36 (t, 2H), 3.73 (m, 2H), 1.76 (q,2H), 1.56 (m, 2H), 1.39 (m, 2H).

EXAMPLE 3074-(((1R)-5-(dimethylamino)-1-((phenylthio)methyl)pentyl)amino)-N-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)benzoyl)-3-nitrobenzenesulfonamideEXAMPLE 307A methyl 4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)benzoate

The desired product was prepared by substituting Example 252E forExample 296A in Example 296B. MS (APCI) m/e 244 (M+H)⁺.

EXAMPLE 307B 4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)benzoic acid

The desired product was prepared by substituting Example 307A forExample 252F in Example 252G. MS (APCI) m/e 230 (M+H)⁺.

EXAMPLE 307C4-(((1R)-5-(dimethylamino)-1-((phenylthio)methyl)pentyl)amino)-N-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)benzoyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 307B forExample 257C in Example 124E. MS (ESI) m/e 664(M+H)⁺, m/e 662 (M−H)⁻; ¹HNMR (500 MHz, DMSO-d₆) δ8.57 (d, 1H), 8.33 (d, 1H), 8.31 (d, 1H), 7.95(d, 2H), 7.92-7.88 (m, 2H), 7.81 (m, 3H), 7.73 (d, 2H), 7.24 (dt, 2H),7.22 (d, 1H), 7.14 (td, 1H), 7.10 (tt, 1H), 6.49 (d, 1H), 4.12 (m, 1H),3.52 (s, 3H), 3.36 (m, 2H), 2.95 (m, 2H), 2.69 (s, 3H), 2.67 (s, 3H),1.77 (q, 2H), 1.64 (m, 2H), 1.36 (m, 2H).

EXAMPLE 3084-(((1R)-5-amino-1-((phenylthio)methyl)pentyl)amino)-N-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)benzoyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 124C andExample 307B for Example 124E and Example 257C, respectively, in Example124F. MS (ESI) m/e 634 (M−H)⁻; ¹H NMR (500 MHz, DMSO-d₆) δ8.57 (d, 1H),8.33 (d, 1H), 8.31 (d, 1H), 7.95 (d, 2H), 7.92-7.88 (m, 2H), 7.81 (m,3H), 7.73 (d, 2H), 7.24 (dt, 2H), 7.22 (d, 1H), 7.14 (td, 1H), 7.10 (tt,1H), 6.49 (d, 1H), 4.12 (m, 1H), 3.52 (s, 3H), 3.36 (t, 2H), 3.73 (m,2H), 1.76 (q, 2H), 1.54 (m, 2H), 1.39 (m, 2H).

EXAMPLE 3093-nitro-N-(4-(3-phenylpyrrolidin-1-yl)benzoyl)-4-((2-(phenylthio)ethyl)amino)benzenesulfonamideEXAMPLE 309A ethyl 4-(2,5-dioxo-3-phenylpyrrolidin-1-yl)benzoate

The desired product was prepared by substituting3-phenyldihydrofuran-2,5-dione for 3,3-dimethylglutaric anhydride inExample 119A. MS (DCI) m/e 324 (M+H)⁺.

EXAMPLE 309B ethyl 4-(3-phenylpyrrolidin-1-yl)benzoate

The desired product was prepared by substituting Example 309A forExample 119A in Example 199B. MS(DCI) m/e 296 (M+H)⁺.

EXAMPLE 309C 4-(3-phenylpyrrolidin-1-yl)benzoic acid

The desired product was prepared by substituting Example 309B forExample 119B in Example 119C. MS (DCI) m/e 268 (M+H)⁺.

EXAMPLE 309D3-nitro-N-(4-(3-phenylpyrrolidin-1-yl)benzoyl)-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 309C andExample 77B for Example 1B and Example 1C, respectively, in Example 1D.MS (ESI(+)) m/e 603 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ11.90 (s, 1H),8.75 (t, 1H), 8.59 (d, 1H), 7.91 (dd, 1H), 7.74 (d, 2H), 7.35 (m, 5H),7.27 (t, 2H), 7.14-7.30 (m, 5H) 6.58 (d, 2H), 3.78 (dd, 1H), 3.66 (m,2H), 3.53 (t, 2H), 3.42 (m, 1H), 3.30 (m, 3H), 2.40 (m, 1H), 2.10 (m,1H).

EXAMPLE 310N-(2-((4-((((4′-fluoro-1,1′-biphenyl-4-yl)carbonyl)amino)sulfonyl)-2-nitrophenyl)amino)-3-(phenylthio)propyl)acetamide

A solution of Example 408 (16 mg, 0.026 mmol) in THF (1 mL) anddichloromethane (0.5 mL) at room temperature was treated with saturatedsodium bicarbonate (0.2 mL) and acetyl chloride (0.1 mL), stirred for 18hours, and concentrated. The concentrate was purified by flash columnchromatography on silica gel with 30-100% ethyl acetate/dichloromethaneto provide the desired product. MS (ESI(−)) m/e 621 (M−H)⁻; ¹H NMR (300MHz, DMSO-d₆) δ8.54 (d, 1H), 8.35 (d, 1H), 8.23 (t, 1H), 7.96 (d, 2H),7.84 (dd, 1H), 7.75 (m, 5H), 7.35-7.10 (m, 7H), 4.05 (m, 1H), 1.74 (t,3H), and remaining protons (4) are buried under solvent peaks.

EXAMPLE 311N-((2,4′-difluoro-1,1′-biphenyl-4-yl)carbonyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamideEXAMPLE 311A methyl 4-bromo-3-fluorobenzoate

A solution of 4-bromo-3-fluorobenzoic acid (117 mg, 0.50 mmol) inmethanol (1 mL) and dichloromethane (2 mL) at room temperature wasslowly treated with 2M trimethylsilyldiazomethane in hexanes until thesolution became light yellow. The mixture was concentrated to providethe desired product.

EXAMPLE 311B methyl 2,4′-difluoro-1,1′-biphenyl-4-carboxylate

The desired product was prepared by substituting Example 311A and4-fluorophenylboronic acid for Example 5A and(4-methoxycarbonylphenyl)boronic acid, respectively, in Example 5B.

EXAMPLE 311CN-((2,4′-difluoro-1,1′-biphenyl-4-yl)carbonyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 311B andExample 77B for Example 5C and Example 3A, respectively, in Example 5D.MS (ESI(−)) m/e 568 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ8.76 (t, 1H),8.61 (d, 1H), 7.94 (dd, 1H), 7.82 (m, 1H), 7.79 (s, 1H), 7.65 (m, 3H),7.40-7.15 (m, 8H), 3.66 (q, 2H), 3.20 (t, 2H).

EXAMPLE 3124-((2-(((ethylamino)carbonyl)amino)-1-((phenylthio)methyl)ethyl)amino)-N-((4′-fluoro-1,1′-biphenyl-4-yl)carbonyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting ethyl isocyanate foracetyl chloride in Example 310. MS (ESI(−)) m/e 650 (M−H)⁻; ¹H NMR (400MHz, methanol-d₄) δ8.74 (d, 1H), 7.93 (m, 3H), 7.68 (m, 4H), 7.31 (m,2H), 7.15 (m, 5H), 7.03 (d, 1H), 4.16 (m, 1H), 3.45 (m, 2H), 3.35 (dd,1H), 3.17 (dd, 1H), 3.05 (q, 2H), 1.01 (7, 3H), and remaining proton isburied under solvent peaks.

EXAMPLE 313N-(4-(4-benzylpiperazin-1-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting benzaldehyde for(1-benzyl-2-oxo-ethyl)-carbamic acid tert-butyl ester in Example 173. MS(ESI(−)) m/e 630 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ8.56 (t, 1H), 8.51(d, 1H), 7.87 (dd, 1H), 7.73 (d, 2H), 7.41-7.26 (m, 8H), 7.21 (d, 2H),7.02 (d, 1H), 6.84 (d, 2H), 3.63 (q, 2H), 3.55 (s, 2H), 3.31-3.20 (m,10H), 2.81 (dd, 1H).

EXAMPLE 314N-(4-(2-(4,4-dimethyl-3-oxopentyl)-1,3-benzothiazol-5-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting 1-bromopinacolone forallyl bromide in Example 213. MS (ESI) m/e 701, 703 (M−H)⁻, (M+H)⁺; ¹HNMR (300 MHz, DMSO-d₆) δ0.95 (s, 3H), 2.52 (t, 2H), 2.73 (s, 3H), 2.89(s, 3H), 3.27 (t, 2H), 3.29 (t,2H), 3.61 (dt, 2H), 7.02 (d, 1H), 7.19(t, 1H), 7.31 (t, 1H), 7.39 (d, 2H), 7.70-7.77 (m, 3H), 7.89 (dd, 1H),7.93-8.02 (m, 3H), 8.12 (d, 1H), 8.24 (s, 1H), 8.53 (d, 1H), 8.55 (t,1H).

EXAMPLE 315N-((4′-fluoro-1,1′-biphenyl-4-yl)carbonyl)-4-(((1S)-3-morpholin-4-yl-3-oxo-1-((phenylthio)methyl)propyl)amino)-3-nitrobenzenesulfonamideEXAMPLE 315A(3S)-3-((4-(aminosulfonyl)-2-nitrophenyl)amino)-4-(phenylthio)butanoicacid

The desired product was prepared by substituting Fmoc-L-Asp(OtBu)-OH forFmoc-D-Asp(OtBu)-OH in Examples 122A-122E.

EXAMPLE 315B4-(((1S)-3-morpholin-4-yl-3-oxo-1-((phenylthio)methyl)propyl)amino)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 315A andmorpholine for Example 122E and dimethylamine in Example 122F.

EXAMPLE 315C N-((4′-fluoro-1,1′-biphenyl-4-yl)carbonyl)-4-(((1S)-3-morpholin-4-yl-3-oxo-1-((phenylthio)methyl)propyl)amino)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 315B forExample 1C in Example 1D. MS (ESI(−)) m/e 677 (M−H)⁻; ¹H NMR (300 MHz,methanol-d₄) δ8.79 (d, 1H), 8.75 (d, 1H), 7.94 (m, 3H), 7.70 (m, 4H),7.30 (m, 2H), 7.24-7.13 (m, 5H), 7.01 (d, 1H), 4.50 (m, 1H), 3.62-3.52(m, 4H), 3.52-3.46 (m, 4H), 3.37 (m, 2H), 3.00 (dd(1H), 2.85 (dd, 1H).

EXAMPLE 316N-(4-(2-(hydroxymethyl)-3-methyl-1-benzothien-5-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

A mixture of Example 351E (40 mg, 0.063 mmol) and NaBH₄ (20 mg) inmethanol at room temperature was stirred for 10 minutes andconcentrated. The concentrate was purified by flash columnchromatography on silica gel with ethyl acetate to provide the desiredproduct. MS (ESI(−)) m/e 632 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ2.38 (s,3H), 3.19 (t, 2H), 3.60 (m, 1H), 4.05 (m, 1H), 4.76 (d, 2H), 5.08 (m,1H), 6.99 (d, 1H), 7.16 (m, 1H), 7.21 (dd, 1H), 7.31 (dd, 2H), 7.39 (dd,2H), 7.66 (m, 1H), 7.71 (d, 1H), 7.87 (d, 2H), 7.97 (dd, 3H), 8.51 (dd,1H), 8.52 (d, 1H).

EXAMPLE 317N-(4-(1-(morpholin-4-ylcarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

A mixture of Example 340A (50 mg, 0.08 mmol), 4-morpholinecarbonylchloride (15 mg, 0.012 mmol), and N,N-diisopropylethylamine (0.07 mL,0.4 mmol) in dichloromethane (0.5 mL) at room temperature was stirredfor 16 hours and concentrated. The concentrate was dissolved in 1:1DMSO/methanol (1.0 mL) and purified by reverse phase preparative HPLCusing 20-95% acetonitrile/0.1% TFA to provide the desired product. MS(ESI(−)) m/e 650 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ8.78 (br t, 1H),8.60 (d, 1H), 7.92 (dd, 1H), 7.85 (d, 2H), 7.55 (d, 2H), 7.40-7.15 (m,6H), 6.35 (m, 1H), 3.92 (d, 2H), 3.70 (m, 2H), 3.60 (t, 4H), 3.40-3.25(m, 6H), 3.15 (t, 4H), 2.79 (s, 3H), 3.10-2.70 (m, 4H), 2.65 (t, 2H).

EXAMPLE 318N-(4-(1,4-dioxa-8-azaspiro(4.5)dec-8-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamideEXAMPLE 318A 4-(1,4-dioxa-8-azaspiro(4.5)dec-8-yl)benzoic acid

The desired product was prepared by substituting Example 158A forExample 119B in Example 119C. MS (DCI) m/e 264 (M+H)⁺.

EXAMPLE 318BN-(4-(1,4-dioxa-8-azaspiro(4.5)dec-8-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 318A andExample 77B for Example 1B and Example 1C, respectively, in Example 1D.MS (ESI(+)) m/e 599 (M+H)⁺; ¹H NMR (300 MHz, CDCl₃) δ8.88 (d, 1H), 8.67(t, 1H), 8.55 (s, 1H), 8.15 (dd, 1H), 7.64 (d, 2H), 7.41 (dd, 2H), 7.30(m, 2H), 6.86 (d, 2H), 6.82 (d, 2H), 3.99 (s, 4H), 3.57 (m, 2H), 3.50(t, 4H), 3.21 (t, 2H), 1.78 (t, 4H).

EXAMPLE 319N-(4-(2,8-bis(trifluoromethyl)quinolin-4-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethylamino)benzenesulfonamide

A solution of Example 214D (100 mg, 0.15 mmol) and2,8-bistrifluoromethyl-3-chloroquinoline (100 mg, 0.343 mmol) in dioxane(2 mL) was treated with Pd₂(dba)₃ (10 mg, 0.011 mmol), P(t-Bu)₃ (20 mg,0.1 mmol) and Cs₂CO₃ (150 mg, 0.50 mmol), purged with argon, sealed, andheated to 85° C. for 18 hours. The mixture was concentrated and theconcentrate was dissolved in 1:1 DMSO/methanol (1 mL) and filtered. Thefiltrate was purified by preparative HPLC (using a Nova-Pak HR C-18column and a solvent system varying in gradient from 10-95%acetonitrile/water containing 0.1% TFA) to provide the desired product.MS (ESI(+)) m/e 721 (M+H)⁺, m/e 719 (M−H)⁻; ¹H NMR (500 MHz, DMSO-d₆)δ8.80 (t, 1H), 8.67 (d, 1H), 8.41 (d, 1H), 8.14 (d, 1H), 8.12 (d, 2H),8.08 (s, 1H), 7.97 (dd, 1H), 7.91 (t, 1H), 7.77 (d, 2H), 7.38 (dt, 2H),7.28 (td, 2H), 7.24 (d, 1H), 7.17 (tt, 1H), 3.69 (q, 2H), 3.31 (t, 2H).

EXAMPLE 3203-nitro-N-(4-(2-(3-oxo-3-piperidin-1-ylpropyl)-1,3-benzothiazol-5-yl)benzoyl)-4-((2-(phenylthio)ethylamino)benzenesulfonamideEXAMPLE 320A tert-butyl 3-(5-bromo-1,3-benzothiazol-2-yl)propanoate

The desired product was prepared by substituting tert-butyl bromoacetatefor allyl bromide in Example 213A.

EXAMPLE 320B 3-(5-bromo-1,3-benzothiazol-2-yl)propanoic acid

The desired product was prepared by substituting Example 320A forExample 201G in Example 201H.

EXAMPLE 320C 5-bromo-2-(3-oxo-3-piperidin-1-ylpropyl)-1,3-benzothiazole

The desired product was prepared by substituting Example 320B andpiperidine for Example 1B and Example 1C, respectively, in Example 1D.

EXAMPLE 320D4-(2-(3-oxo-3-piperidin-1-ylpropyl)-1,3-benzothiazol-5-yl)benzoic acid

The desired product was prepared by substituting Example 320C for6-bromoindole in Example 4A.

EXAMPLE 320E3-nitro-N-(4-(2-(3-oxo-3-piperidin-1-ylpropyl)-1,3-benzothiazol-5-yl)benzoyl)-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 320D andExample 77B for Example 1B and Example 1C, respectively, in Example 1D.MS (ESI) m/e 728, 730 (M−H)⁻(M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ1.42 (t,2H), 1.55 (tt, 4H), 2.93 (t, 2H), 3.28 (t, 2H), 3.36 (t, 2H), 3.44 (t,4H), 3.61 (dt, 2H), 7.01 (d, 1H), 7.19 (t, 1H), 7.31 (t, 2H), 7.39 (d,2H), 7.73 (d, 3H), 7.89 (dd, 1H), 7.98 (d, 2H), 8.10 (d, 1H), 8.19 (s,1H), 8.52 (d, 1H), 8.54 (t, 1H).

EXAMPLE 321N-(4-(3-(cyanomethyl)-1-benzothien-5-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamideEXAMPLE 321A methyl 4-(3-(cyanomethyl)-1-benzothien-5-yl)benzoate

The desired product was prepared by substituting3-cyanomethyl-5-chlorobenzthiophene for5-chloro-2-methyl-1,3-benzoxazole in Example 54A. MS (ESI(+)) m/e 308(M+H)⁺.

EXAMPLE 321B 4-(3-(cyanomethyl)-1-benzothien-5-yl)benzoic acid

The desired product was prepared by substituting Example 321A forExample 1A in Example 1B. MS (ESI(−)) m/e 292 (M−H)⁻.

EXAMPLE 321CN-(4-(3-(cyanomethyl)-1-benzothien-5-yl)-benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 321B andExample 77B for Example 1B and Example 1C, respectively, in Example 1D.MS (ESI(−)) m/e 627 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ3.29 (m, 2H),3.61 (m, 2H), 4.04 (m, 1H), 4.40 (s, 2H), 6.99 (d, 1H), 7.21 (dd, 1H),7.31 (dd, 2H), 7.40 (d, 2H), 7.54 (dd, 2H), 7.56 (d, 1H), 7.91 (d, 1H),8.02 (d, 2H), 8.10 (d, 1H), 8.19 (s, 1H), 8.52 (m, 2H).

EXAMPLE 322N˜2˜-(2-nitro-4-(((4-(1-pentyl-1H-pyrazol-4-yl)benzoyl)amino)sulfonyl)phenyl)-N˜1˜,N˜1˜-bis(4-(N-(2-nitro-4-(((4-(1-pentyl-1H-pyrazol-4-yl)benzoyl)amino)sulfonyl)phenyl)-S-phenylcysteinyl)morpholin-3-yl)-S-phenylcysteinamideEXAMPLE 322A 4-iodo-1-pentyl-1H-pyrazole

The desired product was prepared by substituting 1-iodopentane for1-bromooctane in Example 198A. MS (ESI(+)) m/e 265 (M+H)⁺.

EXAMPLE 322B 4-(1-pentyl-1H-pyrazol-4-yl)benzoic acid

The desired product was prepared by substituting Example 322A for6-bromoindole in Example 4A. MS (ESI(−)) m/e 257 (M−H)⁻.

EXAMPLE 322CN˜2˜-(2-nitro-4-(((4-(1-pentyl-1H-pyrazol-4-yl)benzoyl)amino)sulfonyl)phenyl)-N˜1˜,N˜1˜-bis(4-(N-(2-nitro-4-(((4-(1-pentyl-1H-pyrazol-4-yl)benzoyl)amino)sulfonyl)phenyl)-S-phenylcysteinyl)morpholin-3-yl)-S-phenylcysteinamide

The desired product was prepared by substituting Example 322B andExample 180B for Example 1B and Example 1C, respectively, in Example 1D.MS (ESI(−)) m/e 705 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ0.88 (t, 3H),1.28 (m, 4H), 1.80 (m, 2H), 3.19 (dd, 1H), 3.51 (m, 4H), 3.59 (m, 4H),3.69 (dd, 1H), 4.10 (t, 2H), 5.30 (m, 1H), 7.18 (m, 4H), 7.27 (d, 2H),7.51 (m, 2H), 7.89 (m, 4H), 8.20 (dd, 1H), 8.49 (dd, 1H), 8.95 (d, 1H).

EXAMPLE 323N-(4-(2-(4-acetylpiperazin-1-yl)quinolin-8-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

A solution of 1-acetylpiperazine (100 mg, 0.80 mmol), Example 336E (30mg, 0.08 mmol), and triethyl amine (100 μL) in DMSO (0.5 mL) was heatedto 120° C. for 18 hours, diluted with methanol (0.5 mL), and purified bypreparative HPLC (using a Nova-Pak HR C-18 column and a solvent systemincreasing in gradient from 10-95% acetonitrile/water containing 0.1%)to provide the desired product. MS (ESI) m/e 711, 709 (M+H)⁺, (M−H)⁻; ¹HNMR (500 MHz, DMSO-d₆) δ8.78 (t, 1H), 8.65 (d, 1H), 8.14 (d, 1H), 7.97(d, 2H), 7.95 (d, 1H), 7.86 (d, 2H), 7.77 (dd, 1H), 7.64 (dd, 1H), 7.38(dt, 2H), 7.33 (td, 1H), 7.29 (d, 1H), 7.28 (td, 2H), 7.23 (d, 1H), 7.17(tt, 1H), 3.69 (q, 2H), 3.67-3.50 (m, 8H), 3.31 (t, 2H), 2.02 (s, 3H).

EXAMPLE 324N-(4-(1H-indol-4-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamideEXAMPLE 324A methyl 4-(1H-indol-4-yl)benzoate

The desired product was prepared by substituting 4-bromoindole forExample 5A in Example 5B.

EXAMPLE 324B 4-(1H-indol-4-yl)benzoic acid

The desired product was prepared by substituting Example 324A forExample 1A in Example 1B.

EXAMPLE 324CN-(4-(1H-indol-4-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 324B andExample 77B for Example 1B and Example 1C, respectively, in Example 1D.MS (ESI(−)) m/e 571 (M−H)⁻; ¹H NMR (400 MHz, methanol-d₄) δ8.81 (d, 1H),8.02 (dd, 1H), 7.96 (d, 2H), 7.78 (d, 2H), 7.40 (m, 2H), 7.31 (d, 1H),7.25-7.10 (m, 4H), 7.06 (d, 1H), 6.59 (d, 1H), 3.68 (q, 2H), 3.27 (t,2H).

EXAMPLE 325 2-methoxyethyl4-(4-((((3-nitro-4-((2-(phenylthio)ethyl)amino)phenyl)sulfonyl)amino)carbonyl)phenyl)piperazine-1-carboxylate

A solution of Example 173A (54.1 mg, 0.1 mmol) in pyridine (2 mL) andtriethylamine (1 mL) at room temperature was treated with 2-methoxyethylchloroformate (0.2 mmol), stirred for 18 hours, and concentrated. Theconcentrate was purified by flash column chromatography on silica gelwith 0-5% methanol/dichloromethane) to provide the desired product. MS(ESI(−)) m/e 642 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ8.66 (t, 1H), 8.55(d, 1H), 7.89 (dd, 1H), 7.75 (d, 2H), 7.30-7.40 (m, 2H), 7.31-7.25 (m,2H), 7.21-7.07 (m, 2H), 6.90 (d, 2H), 4.16-4.12 (m, 2H), 3.63 (q, 2H),3.54-3.43 (m, 4H), 3.31-3.20 (m, 8H), 3.23 (s, 3H).

EXAMPLE 326N-(4-(3-formyl-1-benzothien-5-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamideEXAMPLE 326A (5-chloro-1-benzothien-3-yl)methanol

A solution of 3-bromomethyl-5-chlorobenzothiophene (2.5 g, 9.56 mmol)and potassium acetate (1.96 g, 20 mmol) in 1M NaOH (40 mL) and dioxane(40 mL) was heated to reflux for 24 hours, adjusted to pH<7 with 1M HCl,and extracted with ethyl acetate (3×). The combined extracts were washedwith brine, concentrated, and purified by flash column chromatography onsilica gel with 50% ethyl acetate/hexanes to provide the desiredproduct.

EXAMPLE 326B methyl 4-(3-(hydroxymethyl)-1-benzothien-5-yl)benzoate

The desired product was prepared by substituting Example 326A for5-chloro-2-methyl-1,3-benzoxazole in Example 54A. MS (ESI(+)) m/e 299(M+H)⁺.

EXAMPLE 326C methyl 4-(3-formyl-1-benzothien-5-yl)benzoate

A solution of Example 326B (298 mg, 1 mmol) and Dess-Martin periodinane(466 mg, 1.1 mmol) in dichloromethane at room temperature was stirredfor 90 minutes and purified by flash chromatography on silica gel with20% ethyl acetate/hexanes to provide the desired product. MS (ESI(+))m/e 297 (M+H)⁺.

EXAMPLE 326D 4-(3-formyl-1-benzothien-5-yl)benzoic acid

The desired product was prepared by substituting Example 326C forExample 1A in Example 1B. MS (ESI(−)) m/e 281 (M−H)⁻.

EXAMPLE 326EN-(4-(3-formyl-1-benzothien-5-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 326D andExample 77B for Example 1B and Example 1C, respectively, in Example 1D.MS (ESI(−)) m/e 616 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ3.29 (m, 2H),3.69 (m, 2H), 4.00 (m, 1H), 7.19 (dd, 2H), 7.21 (dd, 1H), 7.30 (dd, 2H),7.38 (d, 2H), 7.85 (m, 3H), 7.95 (dd, 1H), 8.01 (d, 2H), 8.24 (d, 1H),8.51 (d, 1H), 8.79 (dd, 1H), 8.82 (d, 1H), 9.02 (s, 1H).

EXAMPLE 327N-(5-(4-chlorophenyl)-2-furoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting5-(4-chlorophenyl)-2-furoic acid and Example 77B for Example 1B andExample 1C, respectively, in Example 1D. MS (ESI(−)) m/e 556 (M−H)⁻; ¹HNMR (300 MHz, DMSO-d₆) δ8.52 (t, 1H), 7.88 (dd, 1H), 7.75 (d, 2H), 7.49(d, 2H), 7.41-7.39 (m, 2H), 7.33-7.29 (m, 2H), 7.22-7.18 (m, 1H),7.01-6.98 (m, 3H), 6.89 (d, 1H), 3.63-3.59 (m, 2H), 3.31-3.20 (m, 2H).

EXAMPLE 328N-((2′-methoxy-4′-(2-(4-methylpiperazin-1-yl)-2-oxoethyl)-1,1′-biphenyl-4-yl)-carbonyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamideEXAMPLE 328A methyl4′-(2,2-dibromovinyl)-2′-methoxy-1,1′-biphenyl-4-carboxylate

A solution of Example 122I (1.35 g, 5.0 mmol) in dichloromethane (30 mL)at room temperature was treated with carbon tetrabromide (1.82 g, 5.5mmol) and triphenylphosphine (2.88 g, 11 mmol), stirred for 1 hour,treated with hexanes (50 mL), and filtered through silica gel (50 g).The solution was rinsed with 1:1 water/dichloromethane, separated, andthe organic phase was concentrated. The concentrate was purified byflash column chromatography on silica gel with 2-10% ethylacetate/hexanes to provide the desired product.

EXAMPLE 328B methyl2′-methoxy-4′-(2-(4-methylpiperazin-1-yl)-2-oxoethyl)-1,1′-biphenyl-4-carboxylate

A mixture of Example 328A (213 mg, 0.5 mmol), 1-methylpiperazine (2.5mmol), and bis(tricyclohexylphosphine)palladium chloride (0.0025 mmol)in DMF (1.5 mL) and water (0.25 mL) was heated to 80° C. for 8 hours,diluted with ethyl acetate (100 mL), washed with water (45 mL) and brine(10 mL), dried (MgSO₄), filtered, and concentrated. The concentrate waspurified by flash column chromatography on silica gel with 2-10%methanol/dichloromethane to provide the desired product.

EXAMPLE 328CN-((2′-methoxy-4′-(2-(4-methylpiperazin-1-yl)-2-oxoethyl)-1,1′-biphenyl-4-yl)carbonyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 328B andExample 77B for Example 5C and Example 3A, respectively, in Example 5D.MS (ESI(−)) m/e 702 (M−H)⁻; ¹H NMR (500 MHz, DMSO-d₆) δ8.78 (t, 1H),8.63 (d, 1H), 7.93 (dd, 1H), 7.90 (d, 2H), 7.59 (d, 2H), 7.36 (m, 2H),7.27 (m, 3H), 7.22 (d, 1H), 7.19 (tt, 1H), 6.99 (d, 1H), 6.90 (dd, 1H),3.82 (s, 2H), 3.75 (s, 3H), 3.68 (q, 2H), 3.29 (t, 4H), 2.82 (s, 3H),remaining 6 protons are buried under very broad water peak (3.60-3.30ppm).

EXAMPLE 3294-((2-morpholin-4-yl-1-((phenylthio)methyl)ethyl)amino)-3-nitro-N-(4-(1-pentyl-1H-pyrazol-4-yl)benzoyl)benzenesulfonamide

The desired product was prepared by substituting Example 322B andracemic Example 146C for Example 1B and Example 1C, respectively, inExample 1D. MS (ESI(−)) m/e 691 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ0.86(t, 3H), 1.28 (m, 4H), 1.79 (m, 2H), 2.38 (m, 2H), 2.44 (m, 2H), 2.62(d, 2H), 3.40 (dd, 1H), 3.52 (m, 4H), 3.59 (m, 4H), 3.69 (dd, 1H), 4.02(m, 1H), 4.09 (t, 2H), 4.16 (m, 1H), 5.30 (m, 1H), 6.98 (d, 1H), 7.12(dd, 1H), 7.21 (dd, 2H), 7.32 (d, 2H), 7.52 (m, 2H), 7.86 (m, 4H), 8.21(s, 1H), 8.36 (d, 1H), 8.48 (s, 1H).

EXAMPLE 3303-(5-(4-((((4-((1-adamantylmethyl)amino)-3-nitrophenyl)sulfonyl)amino)carbonyl)phenyl)-1,3-benzothiazol-2-yl)-N-butylpropanamideEXAMPLE 330A 3-(5-bromo-1,3-benzothiazol-2-yl)-N-butylpropanamide

The desired product was prepared by substituting Example 320B andbutylamine for Example 1B and Example 1C, respectively, in Example 1D.

EXAMPLE 330B4-(2-(3-(butylamino)-3-oxopropyl)-1,3-benzothiazol-5-yl)benzoic acid

The desired product was prepared by substituting Example 330A for6-bromoindole in Example 4A.

EXAMPLE 330C3-(5-(4-((((4-((1-adamantylmethyl)amino)-3-nitrophenyl)sulfonyl)amino)carbonyl)phenyl)-1,3-benzothiazol-2-yl)-N-butylpropanamide

The desired product was prepared by substituting Example 330B andExample 28A for Example 1B and Example 1C, respectively, in Example 1D.MS (ESI) m/e 728, 730 (M−H)⁻, (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ0.82(t, 3H), 1.25 (m, 2H), 1.35 (tt, 2H), 1.55-1.73 (m, 11H), 1.97 (m, 2H),2.65 (t, 2H), 3.04 (dt, 2H), 3.12 (d, 2H), 3.33 (t, 2H), 7.16 (d, 1H),7.71 (d, 2H), 7.73 (d, 1H), 7.90 (dd, 1H), 7.93 (t, 1H), 7.98 (d, 2H),8.10 (d, 1H), 8.18 (s, 1H), 8.38 (t, 1H), 8.54 (d, 1H).

EXAMPLE 331N-(4-(2-(hydroxymethyl)quinolin-8-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

A mixture of Example 339B (10 mg) and sodium borohydride (4 mg) inmethanol (1 mL) was stirred at room temperature for 4 hours, dilutedwith ethyl acetate (30 mL), washed with water (5 mL) and brine (5 mL),dried (MgSO₄), filtered, and concentrated. The concentrate was purifiedby flash column chromatography on silica gel with ethyl acetate toprovide the desired product. MS (ESI(−)) m/e 613 (M−H)⁻; ¹H NMR (400MHz, DMSO-d₆) δ8.77 (d, 2H), 8.33 (d, 1H), 8.09 (d, 2H), 8.00 (dd, 1H),7.91 (dd, 1H), 7.75 (dd, 1H), 7.69 (d,H), 7.51 (m, 2H), 7.39 (m, 2H),7.23 (t, 2H), 7.18 (ttt, 1H), 6.94 (d, 1H), 4.75 (s, 2H), 3.62 (m, 2H),3.24 (t, 2H).

EXAMPLE 332N-((6-(4-fluorophenyl)pyridin-3-yl)carbonyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 77B and Example298B for Example 124E and Example 257C, respectively, in Example 124F.MS (ESI) m/e 553, 551 (M+H)⁺, (M−H)⁻; ¹H NMR (500 MHz, DMSO-d₆) δ9.07(d, 1H), 8.78 (t, 1H), 8.64 (d, 1H), 8.30 (dd, 1H), 8.22 (q, 2H), 8.10(d, 1H), 7.95 (dd, 1H), 7.38-7.16 (m, 8H), 3.67 (q, 2H), 3.29 (t, 2H).

EXAMPLE 333N-(4-(3,5-dimethyl-1-pentyl-1H-pyrazol-4-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamideEXAMPLE 333A 4-bromo-3,5-dimethyl-1-pentyl-1H-pyrazole

The desired product was prepared by substituting 5-iodopentane and4-bromo-3,5-dimethylpyrazole for 1-bromooctane and 4-iodopyrazole,respectively, in Example 198A. MS (ESI(+)) m/e 245, 247 (M+H)⁺.

EXAMPLE 333B 4-(3,5-dimethyl-1-pentyl-1H-pyrazol-4-yl)benzoic acid

The desired product was prepared by substituting Example 333A for6-bromoindole in Example 4A. MS (ESI(−)) m/e 285 (M−H)⁻.

EXAMPLE 333CN-(4-(3,5-dimethyl-1-pentyl-1H-pyrazol-4-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 333B andExample 77B for Example 1B and Example 1C, respectively, in Example 1D.MS (ESI(−)) m/e 620 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ0.89 (t, 3H),1.30 (m, 4H), 1.71 (tt, 2H), 2.11 (s, 3H), 2.21 (s, 3H), 3.27 (t, 2H),3.61 (q, 2H), 3.96 (t, 2H), 4.39 (m, 1H), 6.99 (d, 1H), 7.19 (d, 1H),7.20 (dd, 2H), 7.31 (dd, 2H), 7.40 (d, 2H), 7.89 (dd, 1H), 7.90 (d, 2H),8.51 (d, 1H), 8.52 (t, 1H).

EXAMPLE 3343-nitro-4-((2-(phenylthio)ethyl)amino)-N-(4-quinolin-2-ylbenzoyl)benzenesulfonamide

The desired product was prepared by substituting 2-chloroquinoline andExample 108A for 4-bromo-1-iodobenzene and Example 3C, respectively, inExample 3D. MS (ESI(−)) m/e 583 (M−H)⁻; ¹H NMR (400 MHz, DMSO-d₆) δ8.55(d, 1H), 8.52 (t, 1H), 8.44 (d, 1H), 8.23 (d, 2H), 8.17 (d, 1H), 8.08(d, 1H), 8.05 (d, 2H), 8.00 (d, 1H), 7.90 (t, 1H), 7.78 (dt, 1H), 7.60(m, 2H), 7.40 (dd, 1H), 7.30 (t, 2H), 7.20 (tt, 1H), 7.00 (d, 1H), 3.63(q, 2H), 3.26 (t, 2H).

EXAMPLE 335N-(4-(2-methyl-1,3-benzothiazol-5-yl)benzoyl)-4-((2-morpholin-4-yl-1-((phenylthio)methyl)ethyl)amino)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 17A and Example245A for Example 1B and Example 1C, respectively, in Example 1D. MS(ESI(+)) m/e 704 (M+H)⁺; ¹H NMR (400 MHz, methanol-d₄) δ8.68 (d, 1H),8.10 (m, 3H), 7.96 (d, 1H), 7.91 (dd, 1H), 7.68 (m, 3H), 7.32 (m, 2H),7.13 (m, 3H), 6.93 (d, 1H), 4.11 (m, 1H), 3.63 (t, 4H), 3.39 (dd, 1H),3.21 (dd, 1H), 2.84 (s, 3H), 2.49 (m, 4H).

EXAMPLE 336N-(4-(2-chloroquinolin-8-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamideEXAMPLE 336A 2-hydroxyquinolin-8-yl trifluoromethanesulfonate

A mixture of 2,8-quinolinediol (4.23 g, 26.3 mmol),2-(N,N-bis(trifluoromethylsulfonyl)amino)pyridine (9.4 g, 26.3 mmol) anddiisopropylethylamine (14 mL, 80.5 mmol) in dichloromethane (50 mL) atroom temperature was stirred for 18 hours, diluted with ethyl acetate(200 mL), washed with water (2×50 mL) and brine (50 mL), dried (Na₂SO₄),filtered, and concentrated. The concentrate was purified by flash columnchromatography on silica gel with 1:4 ethyl acetate/hexanes to providethe desired product. MS (APCI) m/e 292 (M−H)⁻.

EXAMPLE 336B methyl 4-(2-hydroxyquinolin-8-yl)benzoate

A mixture of Example 336A (2.93 g, 10 mmol),4-(methoxycarbonyl)phenylboronic acid (1.80 g, 10 mmol), Pd(Ph₃P)₄(0.346 g, 0.3 mmol), and CsF(1.52 g, 10 mmol) in DME (60 mL) andmethanol (30 mL) was heated to reflux for 18 hours and concentrated. Theconcentrate was dissolved in water (50 mL) and ethyl acetate (300 mL)and the organic phase was washed with water (2×50 mL) and brine (50 mL),dried (Na₂SO₄), filtered, and concentrated. The concentrate was purifiedby flash column chromatography on silica gel with 4:1 hexanes/ethylacetate to provide the desired product. MS (APCI) m/e 280, 278 (M+H)⁺,(M−H)⁻.

EXAMPLE 336C methyl 4-(2-chloroquinolin-8-yl)benzoate

A mixture of Example 336B (1.76 g, 6.3 mmol) in POCl₃(50 mL) was heatedto reflux for 30 minutes and concentrated. The concentrate was purifiedthrough a silica gel pad with 4:1 hexanes/ethyl acetate to provide thedesired product. MS (ESI) m/e 298(M+H)⁺.

EXAMPLE 336D 4-(2-chloroquinolin-8-yl)benzoic acid

The desired product was prepared by substituting Example 336C forExample 1A in Example 1B. MS (ESI) m/e 284 (M+H)⁺.

EXAMPLE 336EN-(4-(2-chloroquinolin-8-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 336C andExample 77B for Example 1B and Example 1C, respectively, in Example 1D.MS (ESI(−)) m/e 617 (M−H)⁻; ¹H NMR (400 MHz, DMSO-d₆) δ8.77 (t, 1H),8.54 (d,2H), 8.52 (d, 1H), 8.11 (dd, 1H), 7.97 (d, 2H), 7.90 (dd, 1H),7.87 (dd, 1H), 7.75 (m, 3H), 7.63 (d, 1H), 7.37 (m, 1H), 7.27 (tt, 2H),7.21 (d, 1H), 7.19 (t, 1H), 3.67 (q, 2H), 3.28 (t, 2H).

EXAMPLE 3373-nitro-N-(4-((E)-2-phenylethenyl)benzoyl)-4-((2-(phenylthio)ethyl)amino)benzenesulfonamideEXAMPLE 337A methyl 4-((E)-2-phenylethenyl)benzoate

The desired product was prepared by substituting beta-styryl boronicacid for 4-fluorophenylboronic acid in Example 1A. MS (ESI(−)) m/e 237(M−H)⁻.

EXAMPLE 337B 4-((E)-2-phenylethenyl)benzoic acid

The desired product was prepared by substituting Example 337A forExample 1A in Example 1B. MS (ESI(−)) m/e 223 (M−H)⁻.

EXAMPLE 337C3-nitro-N-(4-((E)-2-phenylethenyl)benzoyl)-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 337B andExample 77B for Example 1B and Example 1C, respectively, in Example 1D.MS (ESI(−)) m/e 558 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ3.27 (t, 2H),3.61 (t, 2H), 4.01 (m, 1H), 6.99 (d, 1H), 7.20 (d, 1H), 7.27 (d, 2H),7.29 (d, 2H), 7.34 (d, 1H), 7.39 (s, 1H), 7.40 (d, 2H), 7.54 (d, 2H),7.61 (d, 2H), 7.88 (d, 2H), 7.89 (d, 2H), 8.51 (d, 1H), 8.52 (t, 1H).

EXAMPLE 338 tert-butyl3-((4-((((4′-fluoro-1,1′-biphenyl-4-yl)carbonyl)amino)sulfonyl)-2-nitrophenyl)amino)-4-(phenylthio)butanoateEXAMPLE 338A tert-butyl3-((4-(aminosulfonyl)-2-nitrophenyl)amino)-4-(phenylthio)butanoate

The desired product was prepared by substituting Fmoc-DL-Asp(OtBu)-OHfor Fmoc-D-Asp(OtBu)-OH in Examples 122A-122D.

EXAMPLE 338B tert-butyl3-((4-((((4′-fluoro-1,1′-biphenyl-4-yl)carbonyl)amino)sulfonyl)-2-nitrophenyl)amino)-4-(phenylthio)butanoate

The desired product was prepared by substituting Example 338A forExample 1C in Example 1D. MS (ESI(−)) m/e 664 (M−H)⁻; ¹H NMR (300 MHz,methanol-d₄) δ8.73 (d, 1H), 8.58 (d, 1H), 7.95 (dd, 1H), 7.93 (d, 2H),7.70 (m, 4H), 7.28 (m, 2H), 7.23-7.12 (m, 5H), 6.98 (d, 1H), 4.40 (m,1H), 2.78 (m, 2H), 1.36 (s, 9H), and remaining two protons are buriedunder solvent peaks (3.35-3.28 ppm).

EXAMPLE 339N-(4-(2-formylquinolin-8-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamideEXAMPLE 339A 2-formylquinolin-8-yl trifluoroacetate

The desired product was prepared by substituting8-hydroxyquinoline-2-carboxaldehyde for vanillin in Example 122H.

EXAMPLE 339BN-(4-(2-formylquinolin-8-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 339A forExample 389A in Example 389B. MS (ESI(−)) m/e 611 (M−H)⁻; ¹H NMR (500MHz, DMSO-d₆) δ9.97 (s, 1H), 8.66 (d, 1H), 8.54 (d, 1H), 8.52 (t, 1H),8.12 (dd, 1H), 8.02 (d, 2H), 7.95 (s, 1H), 7.93 (dt, 1H), 7.87 (dd, 1H),7.72 (d, 2H), 7.41 (td, 2H), 7.32 (t, 2H), 7.21 (tt, 1H), 7.01 (d, 1H),3.62 (q, 2H), 3.28 (t, 2H).

EXAMPLE 3403-nitro-4-((2-(phenylthio)ethyl)amino)-N-(4-(1-(pyridin-3-ylmethyl)-1,2,3,6-tetrahydropyridin-4-yl)benzoyl)benzenesulfonamideEXAMPLE 340AN-((3-nitro-4-((2-(phenylsulfanyl)ethyl)amino)phenyl)sulfonyl)-4-(1,2,3,6-tetrahydropyridin-4-yl)benzamide

A room temperature mixture of Example 455C in TFA (10 mL) anddichloromethane (10 mL) was stirred for 30 minutes and concentrated toprovide the desired product. MS (ESI(+)) m/e 539 (M+H)⁺.

EXAMPLE 340B3-nitro-4-((2-(phenylthio)ethyl)amino)-N-(4-(1-(pyridin-3-ylmethyl)-1,2,3,6-tetrahydropyridin-4-yl)benzoyl)benzenesulfonamide

A mixture of Example 340A (65 mg, 0.1 mmol), NaBH₃CN (48 mg, 0.75 mmol),2N NaOH (0.15 mL), and 3-pyridinecarboxaldehyde (214 mg, 2 mmol) inacetic acid (0.5 mL) and methanol (1 mL) was stirred for 16 hours. Thereaction mixture was concentrated, dissolved in 1:1 DMSO/methanol (1.0mL) and purified by reverse phase preparative HPLC using 20-90%acetonitrile/water containing 0.1% TFA to provide the desired product.MS (ESI(−)) m/e 628 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ8.78 (br t, 1H),8.70 (d, 1H), 8.70 (dd, 1H), 8.60 (d, 1H), 8.05 (m, 1H), 7.95 (d, 2H),7.62 (d, 2H), 7.60 (dd, 1H), 7.40-7.15 (m, 6H), 6.35 (m, 1H), 4.52 (d,2H), 3.92 (m, 4H), 3.45 (t, 4H), 2.82 (m, 2H).

EXAMPLE 3413-(5-(4-((((3-nitro-4-((2-(phenylthio)ethyl)amino)phenyl)sulfonyl)amino)carbonyl)phenyl)-1,3-benzothiazol-2-yl)-N-(thien-2-ylmethyl)propanamide

The desired product was prepared by substituting thiophene-2-methylaminefor piperidine in Example 320. MS (ESI) m/e 756, 758 (M−H)⁻, (M+H)⁺; ¹HNMR (300 MHz, DMSO-d₆) δ2.18 (t, 2H), 2.74 (t, 2H), 3.28 (t, 2H), 3.63(dt, 2H), 4.44 (d, 2H), 6.88-6.95 (m, 2H), 7.08 (d, 1H), 7.19 (t, 2H),7.29 (t, 2H), 7.35 (dd, 1H), 7.39 (d, 2H), 7.75 (dd, 1H), 7.78 (d, 2H),7.92 (dd, 1H), 7.99 (d, 2H), 8.12 (d, 1H), 8.21 (s, 1H), 8.56 (d, 1H),8.58-8.65 (m, 2H).

EXAMPLE 342N-(4-(4-methylpyridin-2-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting2-chloro-4-methylpyridine for 2,8-bistrifluoromethyl-3-chloroquinolinein Example 319. MS (ESI) m/e 549, 547 (M+H)⁺, (M−H)⁻; ¹H NMR(500 MHz,DMSO-d₆) δ8.78 (t, 1H), 8.64 (d, 1H), 8.54 (d, 1H), 8.19 (d, 2H), 7.98(d, 2H), 7.94 (dd, 1H), 7.92 (d, 1H), 7.37 (dt, 2H), 7.27 (td, 2H), 7.25(dd, 1H), 7.22 (d, 1H), 7.17 (tt, 1H), 3.67 (q, 2H), 3.29 (t, 2H), 2.40(s, 3H).

EXAMPLE 343N-(4-(2-butyl-1-cyclopentyl-1H-benzimidazol-5-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamideEXAMPLE 343A 4-bromo-N¹-cyclopentylbenzene-1,2-diamine

The desired product was prepared by substituting cyclopentylamine forbutylamine in Examples 166A and 166B.

EXAMPLE 343B 5-bromo-2-butyl-1-cyclopentyl-1H-benzimidazole

Valeric acid (8 mL) and Example 343A (250 mg, 0.98 mmol) was heated to160° C. for 18 hours, treated with 1M NaOH (10 mL), extracted with ethylacetate (3×50 mL), washed with brine (10 mL), dried (Na₂SO₄), filtered,and concentrated to provide the desired product.

EXAMPLE 343CN-(4-(2-butyl-1-cyclopentyl-1H-benzimidazol-5-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 343B andExample 214E for 6-bromoindole and 4-(dihydroxyboryl)benzoic acid,respectively, in Example 4A. MS (ESI(+)) m/e 698 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ0.95 (t, 3H), 1.43 (dt, 2H), 1.76 (m, 4H), 2.00 (m, 2H),2.11 (m, 4H), 2.94 (t, 2H), 3.27 (t, 2H), 3.62 (dt, 2H), 4.93 (tt, 1H),7.04 (d, 1H), 7.19 (t, 1H), 7.30 (t, 2H), 7.39 (d, 1H), 7.45-7.64 (m,4H), 7.69 (d, 2H), 7.90 (dd, 1H), 7.95 (d, 2H), 8.54 (d, 1H), 8.58 (t,1H).

EXAMPLE 344N-(4-(6-chloropyrazin-2-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting 2,6-dichloropyrazinefor 2,8-bistrifluoromethyl-3-chloroquinoline in Example 319. MS (ESI(+))m/e 570, 568 (M+H)⁺, (M−H)⁻; ¹H NMR (500 MHz, DMSO-d₆) δ9.35 (s, 1H),8.81 (s, 1H), 8.78 (t, 1H), 8.64 (d, 1H), 8.24 (d, 2H), 8.04 (d, 2H),7.94 (dd, 1H), 7.37 (dt, 2H), 7.27 (td, 2H), 7.22 (d, 1H), 7.17 (tt,1H), 3.68 (q, 2H), 3.29 (t, 2H).

EXAMPLE 345 tert-butyl5-((4-((((4′-fluoro-1,1′-biphenyl-4-yl)carbonyl)amino)sulfonyl)-2-nitrophenyl)amino)-6-(phenylthio)hexylcarbamateEXAMPLE 345A 9H-fluoren-9-ylmethyl1-(hydroxymethyl)-5-(tert-butoxycarbonylamino)pentylcarbamate

The desired product was prepared by substituting Fmoc-DL-Lys(BOC)-OH forFmoc-D-Asp(OtBu)-OH in Example 122A.

EXAMPLE 345B9H-fluoren-9-ylmethyl1-(phenylthiomethyl)-5-(tert-butoxycarbonylamino)pentylcarbamate

The desired product was prepared by substituting Example 345A forExample 122A in Example 122B.

EXAMPLE 345C tert-butyl5-((4-(aminosulfonyl-2-nitrophenyl)amino)-6-(phenylthio)hexylcarbamate

The desired product was prepared by substituting Example 345B forExample 122B in Example 122D.

EXAMPLE 345D tert-butyl5-((4-((((4′-fluoro-1,1′-biphenyl-4-yl)carbonyl)amino)sulfonyl)-2-nitrophenyl)amino)-6-(phenylthio)hexylcarbamate

The desired product was prepared by substituting Example 345C forExample 1C in Example 1D. MS (ESI(−)) m/e 721 (M−H)⁻; ¹H NMR (300 MHz,DMSO-d₆) δ8.48 (d, 1H), 8.17 (d, 1H), 7.97 (d, 2H), 7.82 (dd, 1H), 7.73(m, 2H), 7.61 (d, 2H), 7.32-7.10 (m, 8H), 4.12 (m, 1H), 3.67 (m, 2H),2.74 (m, 2H), 1.75 (m, 2H), 1.53 (m, 2H), 1.40 (m, 2H) 1.32 (s, 9H).

EXAMPLE 346 ethylN-(((2-((4-((((4′-fluoro-1,1′-biphenyl-4-yl)carbonyl)amino)sulfonyl)-2-nitrophenyl)amino)-3-(phenylthio)propyl)amino)carbonyl)glycinate

The desired product was prepared by substituting ethyl isocyanatoacetatefor acetyl chloride in Example 310. MS (ESI(−)) m/e 708 (M−H)⁻; ¹H NMR(300 MHz, DMSO-d₆) δ8.59 (d, 1H), 8.42 (d, 1H), 7.97 (d, 2H), 7.87 (dd,1H), 7.78 (m, 4H), 7.35-7.10 (m, 7H), 6.55 (t, 1H), 6.29 (t, 1H), 4.34(m, 1H), 4.02 (q, 2H), 3.72 (d, 2H), 3.37 (m, 2H, 1.17 (t, 3H), andremaining protons (4) are buried under solvent peaks.

EXAMPLE 347 methyl5-ethyl-2-(4-((((3-nitro-4-((2-(phenylthio)ethyl)amino)phenyl)sulfonyl)amino)carbonyl)phenyl)-1,3-thiazole-4-carboxylateEXAMPLE 347A 4-(5-ethyl-4-(methoxycarbonyl)-1,3-thiazol-2-yl)benzoicacid

The desired product was prepared by substituting methyl2-bromo-5-ethylthiazole-4-carboxylate (prepared according to theprocedure described in J. Chem. Soc. Perkin I 1982, 159-164) for6-bromoindole in Example 4A.

EXAMPLE 347B methyl5-ethyl-2-(4-((((3-nitro-4-((2-(phenylthio)ethyl)amino)phenyl)sulfonyl)amino)carbonyl)phenyl)-1,3-thiazole-4-carboxylate

The desired product was prepared by substituting Example 347A andExample 77B for Example 1B and Example 1C, respectively, in Example 1D.MS (ESI) m/e 625, 627 (M−H)⁻, (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ1.31(t, 3H), 3.25 (t, 2H), 3.28 (q, 2H), 3.62 (dt, 2H), 3.86 (s, 3H), 7.03(d, 1H), 7.19 (t, 1H), 7.30 (t, 2H), 7.39 (d, 2H), 7.88 (d, 2H), 7.99(d, 2H), 8.54 (d, 1H), 8.56 (t, 1H).

EXAMPLE 348N,N-dimethyl-4-(4-((((3-nitro-4-((2-(phenylthio)ethyl)amino)phenyl)sulfonyl)amino)carbonyl)phenyl)-1H-pyrazole-1-sulfonamideEXAMPLE 348A 4-iodo-N,N-dimethyl-1H-pyrazole-1-sulfonamide

The desired product was prepared by substituting dimethylaminosulfonylchloride for 1-bromooctane in Example 198A. MS (ESI(−)) m/e 300 (M−H)⁻.

EXAMPLE 348B 4-(1-((dimethylamino)sulfonyl)-1H-pyrazol-4-yl)benzoic acid

The desired product was prepared by substituting Example 348A for6-bromoindole in Example 4A. MS (ESI(−)) m/e 294 (M−H)⁻.

EXAMPLE 348CN,N-dimethyl-4-(4-((((3-nitro-4-((2-(phenylthio)ethyl)amino)phenyl)sulfonyl)amino)carbonyl)phenyl)-1H-pyrazole-1-sulfonamide

The desired product was prepared by substituting Example 348B andExample 77B for Example 1B and Example 1C, respectively, in Example 1D.MS (ESI(−)) m/e 629 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ2.89 (s, 6H),3.28 (t, 2H), 3.61 (dt, 2H), 3.64 (dt, 2H), 7.01 (d, 1H), 7.20 (t, 1H),7.30 (t, 2H), 7.40 (d, 2H), 7.72 (d, 2H), 7.89 (d, 1H), 7.90 (d, 2H),8.41 (s, 1H), 8.51 (d, 1H), 8.54 (t, 1H), 8.78 (s, 1H).

EXAMPLE 349N-(4-(1-cyclopentyl-1H-benzimidazol-5-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamideEXAMPLE 349A 4-bromo-N¹-cyclopentylbenzene-1,2-diamine

The desired product was prepared by substituting cyclopentylamine forbutylamine in Examples 166A and 166B.

EXAMPLE 349B 5-bromo-1-cyclopentyl-1H-benzimidazole

The desired product was prepared by substituting Example 349A forExample 170A in Example 170B.

EXAMPLE 349CN-(4-(1-cyclopentyl-1H-benzimidazol-5-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 349B andExample 214E for 6-bromoindole and 4-(dihydroxyboryl)benzoic acid,respectively, in Example 4A. MS (ESI) m/e 640, 642 (M−H)⁻, (M+H)⁺; ¹HNMR (300 MHz, DMSO-d₆) δ1.75 (m, 2H), 1.85-2.06 (m, 4H), 2.23 (m, 2H),3.28 (t, 2H), 3.61 (dt, 2H), 4.89 (tt, 1H), 6.99 (d, 1H), 7.19 (t, 1H),7.31 (t, 2H), 7.38 (d, 2H), 7.53 (dd, 1H), 7.56-7.72 (m, 4H), 7.88 (dd,1H), 7.95 (t, 2H), 8.35 (s, 1H), 8.53 (t, 1H), 8.54 (d, 1H).

EXAMPLE 3503-(5-(4-((((4-((1-adamantylmethyl)amino)-3-nitrophenyl)sulfonyl)amino)carbonyl)phenyl)-1,3-benzothiazol-2-yl)-N-(thien-2-ylmethyl)propanamideEXAMPLE 350A3-(5-bromo-1,3-benzothiazol-2-yl)-N-(thien-2-ylmethyl)propanamide

The desired product was prepared by substituting Example 320B andthiophene-2-methylamine for Example 1B and Example 1C, respectively, inExample 1D.

EXAMPLE 350B4-(2-(3-oxo-3-((thien-2-ylmethyl)amino)propyl)-1,3-benzothiazol-5-yl)benzoicacid

The desired product was prepared by substituting Example 350A for6-bromoindole in Example 4A.

EXAMPLE 350C3-(5-(4-((((4-((1-adamantylmethyl)amino)-3-nitrophenyl)sulfonyl)amino)carbonyl)phenyl)-1,3-benzothiazol-2-yl)-N-(thien-2-ylmethyl)propanamide

The desired product was prepared by substituting Example 350B andExample 28A for Example 1B and Example 1C, respectively, in Example 1D.MS (ESI) m/e 768, 770 (M−H)⁻, (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆)δ1.54-1.75 (m, 13H), 1.94-2.02 (m, 2H), 3.14 (d, 2H), 3.75 (t, 2H), 4.44(d, 2H), 6.88-6.96 (m, 2H), 7.16 (d, 1H), 7.35 (dd, 1H), 7.68-7.76 (m,3H), 7.89 (dd, 1H), 7.98 (d, 2H), 8.11 (d, 1H), 8.18 (s, 1H), 8.39 (t,1H), 853 (d, 1H), 8.63 (t, 1H).

EXAMPLE 351N-(4-(2-formyl-3-methyl-1-benzothien-5-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamideEXAMPLE 351A 5-chloro-3-methyl-2-vinyl-1-benzothiophene

A solution of 2-bromo-5-chloro-3-methylbenzthiophene (5 g, 19.1 mmol),vinyltributylstannane (5.59 mL, 19.1 mmol), Pd₂dba₃ (525 mg, 0.57 mmol),and tri(2-furyl)phosphine (532 mg, 2.29 mmol) in NMP (70 mL) at 90° C.was stirred for 18 hours and concentrated. The concentrate was purifiedby flash column chromatography on silica gel with hexanes to provide thedesired product. MS (ESI(−)) m/e 207 (M−H)⁻.

EXAMPLE 351B methyl 4-(3-methyl-2-vinyl-1-benzothien-5-yl)benzoate

The desired product was prepared by substituting Example 351A for5-chloro-2-methyl-1,3-benzoxazole in Example 54A. MS (ESI(+)) m/e 310(M+H)⁺.

EXAMPLE 351C methyl 4-(2-formyl-3-methyl-1-benzothien-5-yl)benzoate

A mixture of Example 351B (900 mg, 3 mmol), 0.08M OsO₄ in tert-butanol(4 mL) and N-morpholine-N-oxide (352 mg, 3 mmol) in THF (25 mL) andwater (10 mL) at room temperature was stirred for 18 hours andpartitioned between water and ethyl acetate. The organic phase wasconcentrated and the concentrate was purified by flash columnchromatography on silica gel with 50% ethyl acetate/hexanes.

A mixture of the purified product (500 mg, 1.5 mmol) and NaIO₄ (500 mg,2.3 mmol) in 1:1 THF/water (40 mL) at room temperature was stirred for 3hours, poured into 1M HCl, and extracted with ethyl acetate (3×). Thecombined extracts were washed with brine and concentrated.

EXAMPLE 351D 4-(2-formyl-3-methyl-1-benzothien-5-yl)benzoic acid

The desired product was prepared by substituting Example 351C forExample 1A in Example 1B. MS (ESI(−)) m/e 295 (M−H)⁻.

EXAMPLE 351EN-(4-(2-formyl-3-methyl-1-benzothien-5-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 351D andExample 77B for Example 1B and Example 1C, respectively, in Example 1D.MS (ESI(−)) m/e 630 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ2.89 (d, 3H),3.29 (t, 2H), 3.69 (dt, 2H), 7.19 (m, 2H), 7.26 (dd, 2H), 7.38 (d, 2H),7.95 (m, 4H), 8.00 (dd, 2H), 8.16 (d, 1H), 8.39 (d, 1H), 8.63 (d, 1H),8.79 (dd, 1H), 10.38 (s, 1H).

EXAMPLE 352N-(4-(4-(cyclohexylcarbonyl)piperazin-1-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting cyclohexanoyl chloridefor 2-methoxyethyl chloroformate in Example 325. MS (ESI(−))m/e 650(M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ8.76 (t, 1H), 8.59 (d, 1H), 7.91 (dd,1H), 7.76 (d, 2H), 7.39-7.34 (m, 2H), 7.29-7.24 (m, 2H), 7.21-7.14 (m,2H), 6.94 (d, 2H), 3.70-3.56 (m, 4H), 3.32-3.23 (m, 8H), 2.60-2.56 (m,1H), 1.72-1.63 (m, 4H), 1.36-1.17 (m, 6H).

EXAMPLE 353 dimethyl1-(2-((4-((((4′-fluoro-1,1′-biphenyl-4-yl)carbonyl)amino)sulfonyl)-2-nitrophenyl)amino)-3-(phenylthio)propyl)-1H-1,2,3-triazole-4,5-dicarboxylate

A solution of Example 434D (40 mg) and dimethyl acetylenedicarboxylate(100 mg) in toluene (2 mL) was heated to 90° C. for 16 hours andpurified by flash column chromatography on silica gel with 30-100% ethylacetate/hexanes to provide the desired product. MS (ESI(−)) m/e 747(M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ8.45 (d, 1H), 8.17 (d, 1H), 7.94 (d,2H), 7.73 (m, 3H), 7.59 (d, 2H), 7.32-7.15 (m, 8H), 5.00 (m, 2H), 4.51(m, 1H), 3.80 (s, 3H), 3.75 (s, 3H), 3.45 (m, 2H).

EXAMPLE 354N-(4-(2-(3-(4-methylpiperazin-1-yl)-3-oxopropyl)-1,3-benzothiazol-5-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting 1-methylpiperazine forpiperidine in Example 320. MS (ESI) m/e 743, 745 (M−H)⁻, (M+H)⁺; ¹H NMR(300 MHz, DMSO-d₆) δ2.43 (s, 3H), 2.68 (m, 4H), 2.97 (t, 2H), 3.17 (d,2H), 3.27 (t, 2H), 3.38)t, 2H), 3.61 (m, 4H), 4.44 (d, 2H), 6.99 (d,1H), 7.21 (tt, 2H), 7.32 (t, 2H), 7.40 (dd, 2H), 7.71 (d, 1H), 7.74 (dd,1H), 7.88 (dd, 1H), 7.98 (d, 2H), 8.10 (d, 1H), 8.18 (d, 1H), 8.62 (t,1H), 8.63 (d, 1H).

EXAMPLE 3554-((2-adamantylmethyl)amino)-N-(4-(2-aminoquinolin-8-yl)benzoyl)-3-nitrobenzenesulfonamideEXAMPLE 355A 2-aminoquinolin-8-yl trifluoroacetate

The desired product was prepared by substituting2-amino-8-hydroxyquinoline for vanillin in Example 122H.

EXAMPLE 355B4-((2-adamantylmethyl)amino)-N-(4-(2-aminoquinolin-8-yl)benzoyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 255A andExample 355A for Example 108A and Example 389A, respectively, in Example389B. MS (ESI(−)) m/e 610 (M−H)⁻; ¹H NMR (400 MHz, DMSO-d₆) δ8.73 (d,1H), 8.50 (t, 1H), 8.12 (br s, 1H), 7.97 (d, 2H), 7.93 (dd, 1H), 7.77(br s, 1H), 7.62 (d, 2H), 7.53 (d, 1H), 7.32 (br s, 1H), 7.30 (d, 1H),6.90 (br s, 1H), 3.17 (d, 2H), 1.98 (m, 3H), 1.72-1.55 (m, 12H).

EXAMPLE 356N-((4′-fluoro-1,1′-biphenyl-4-yl)carbonyl)-4-((3-hydroxy-1-((phenylthio)methyl)propyl)amino)-3-nitrobenzenesulfonamideEXAMPLE 356A3-((4-(aminosulfonyl)-2-nitrophenyl)amino)-4-(phenylthio)butanoic acid

The desired product was prepared by substituting Fmoc-DL-Asp(OtBu)-OHfor Fmoc-D-Asp(OtBu)-OH in Examples 122A-122E.

EXAMPLE 356BN-((4′-fluoro-1,1′-biphenyl-4-yl)carbonyl)-4-((3-hydroxy-1-((phenylthio)methyl)propyl)amino)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 356A forExample 122E in Example 280. MS (ESI(−)) m/e 594 (M−H)⁻; ¹H NMR (500MHz, methanol-d₄) δ8.72 (d, 1H), 7.92 (m, 3H), 7.70 (m, 4H), 7.26 (m,2H), 7.18 (tt, 2H), 7.11 (m, 3H), 7.00 (d, 1H), 4.25 (m, 1H), 3.68 (m,2H), 3.39 (d, 1H), 3.21 (m, 3H), 2.08 (m, 1H), 1,97 (m, 1H).

EXAMPLE 357 methyl4-(4-((((3-nitro-4-((2-(phenylthio)ethyl)amino)phenyl)sulfonyl)amino)carbonyl)phenyl)-3,6-dihydropiridine-1(2H)-carboxylate

The desired product was prepared by substituting methyl chloroformatefor 4-morpholinecarbonyl chloride in Example 317. MS (ESI(−)) m/e 595(M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ8.78 (br t, 1H), 8.60 (d, 1H), 7.92(dd, 1H), 7.85 (d, 2H), 7.55 (d, 2H), 7.40-7.15 (m, 6H), 6.35 (m, 1H),4.08 (d, 2H), 3.70 (m, 2H), 3.62 (s, 3H), 3.60 (t, 2H), 3.40-3.25 (m,4H).

EXAMPLE 358N-(4-(4-((benzyloxy)acetyl)piperazin-1-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting benzyloxyacetylchloride for 2-methoxyethyl chloroformate in Example 325. MS (ESI(−))m/e 688 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ8.74 (t, 1H), 8.59 (d, 1H),7.90 (dd, 1H), 7.76 (d, 2H), 7.39-7.14 (m, 11H), 6.94 (d, 2H), 4.52 (s,2H), 4.24 (s, 2H), 3.66 (q, 2H), 3.70-3.56 (m, 4H), 3.32-3.23 (m, 6H).

EXAMPLE 359N-(4-(1-(2,2-dimethylpropanoyl)-1,2,3,6-tetrahydropyridin-4-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting trimethylacetylchloroformate for 4-morpholinecarbonyl chloride in Example 317. MS(ESI(−)) m/e 621 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ8.78 (br t, 1H),8.60 (d, 1H), 7.92 (dd, 1H), 7.85 (d, 2H), 7.55 (d, 2H), 7.40-7.15 (m,6H), 6.35 (m, 1H), 4.18 (d, 2H), 3.75 (t, 2H), 3.70 (m, 2H), 3.40-3.25(m, 4H), 1.25 (s, 9H).

EXAMPLE 360N-(4-(2-((ethylthio)methyl)-1,3-benzothiazol-5-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting diethyl disulfide forallyl bromide in Example 213. MS (ESI) m/e 663, 665 (M−H)⁻, (M+H)⁺; ¹HNMR (300 MHz, DMSO-d₆) δ1.22 (t, 3H), 2.61 (q, 2H), 3.27 (t, 2H), 3.62(dt, 2H), 4.25 (s, 2H), 7.03 (d, 1H), 7.19 (tt, 1H), 7.30 (td, 2H), 7.40(dd, 1H), 7.75 (d, 2H), 7.76 (dd, 1H), 7.90 (dd, 1H), 7.98 (d, 2H), 8.14(d, 1H), 8.23 (d, 1H), 8.54 (d, 1H), 8.56 (t, 1H).

EXAMPLE 361N-(4-(1-cyclopentyl-2-(2-methoxyethyl)-1H-benzimidazol-5-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting 3-methoxypropionic acidfor valeric acid in Example 343. MS (ESI) m/e 698, 700 (M−H)⁻, (M+H)⁺;¹H NMR (300 MHz, DMSO-d₆) δ1.76 (m, 2H), 1.99 (m, 2H), 2.12 (m, 4H),3.19 (t, 2H), 3.26 (t, 2H), 3.28 (s, 3H), 3.62 (dt, 2H), 3.38 (t, 2H),4.96 (tt, 1H), 7.02 (d, 1H), 7.20 (tt, 1H), 7.31 (td, 2H), 7.40 (dd,2H), 7.48 (dd, 1H), 7.57 (d, 1H), 7.65 (d, 2H), 7.85 (d, 2H), 7.89 (dd,1H), 7.96 (d, 2H), 8.53 (d, 1H), 8.55 (t, 1H).

EXAMPLE 362N-((2′-methoxy-4′-(3-(4-methylpiperazin-1-yl)-3-oxopropyl)-1,1′-biphenyl-4-yl)carbonyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamideEXAMPLE 362A methyl2′-methoxy-4′-(3-(4-methylpiperazin-1-yl)-3-oxopropyl)-1,1′-biphenyl-4-carboxylate

The desired product was prepared by substituting 1-methylpiperazine formorpholine in Example 122M. MS (ESI(−)) m/e 716 (M−H)⁻; ¹H NMR (300 MHz,DMSO-d₆) δ8.79 (t, 1H), 8.63 (d, 1H), 7.94 (dd, 1H), 7.88 (d, 2H), 7.57(d, 2H), 7.37 (m, 2H), 7.30-7.14 (m, 5H), 7.02 (d, 1H), 6.92 (dd, 1H),3.76 (s, 3H), 3.67 (q, 2H), 3.44 (m, 4H), 3.28 (t, 2H), 2.85 (t, 2H),2.80 (s, 3H), 2.72 (t, 2H), and the 8 remaining protons are buried undera very broad water peak (3.75-3.40 ppm).

EXAMPLE 362BN-((2′-methoxy-4′-(3-(4-methylpiperazin-1-yl)-3-oxopropyl)-1,1′-biphenyl-4-yl)carbonyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 362A andExample 77B for Example 5C and Example 3A, respectively, in Example 5D.

EXAMPLE 363N-(4-(1-methyl-1H-benzimidazol-5-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting methylamine forcyclopentylamine in Example 349. MS (ESI) m/e 586, 588 (M−H)⁻, (M+H)⁺;¹H NMR (300 MHz, DMSO-d₆) δ3.28 (t, 2H), 3.60 (dt, 2H), 3.87 (s, 3H),6.98 (d, 1H), 7.19 (tt, 1H), 7.32 (t, 2H), 7.40 (d, 2H), 7.47-7.68 (m,5H), 7.88 (dd, 1H), 7.95 (t, 2H), 8.21 (s, 1H), 8.51 (t, 1H), 8.52 (d,1H),

EXAMPLE 364 ethyl4-(4-((((3-nitro-4-((2-(phenylthio)ethyl)amino)phenyl)sulfonyl)amino)carbonyl)phenyl)piperazine-1-carboxylate

The desired product was prepared by substituting benzyloxyacetylchloride for 2-methoxyethyl chloroformate in Example 325. MS (ESI(−))m/e 612 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ8.71 (t, 1H), 8.57 (d, 1H),7.88 (dd, 1H), 7.76 (d, 2H), 7.39-7.35 (m, 2H), 7.23-7.29 (m, 2H),7.20-7.14 (m, 2H), 6.92 (d, 2H), 4.06 (q, 2H), 3.65 (q, 2H), 3.50-3.46(m, 4H), 3.32-3.23 (m, 6H), 1.20 (t, 3H).

EXAMPLE 365N-(4-(3-methyl-2-vinyl-1-benzothien-5-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamideEXAMPLE 365A 4-(3-methyl-2-vinyl-1-benzothien-5-yl)benzoic acid

The desired product was prepared by substituting Example 351B forExample 1A in Example 1B. MS (ESI(−)) m/e 293 (M−H)⁻.

EXAMPLE 365BN-(4-(3-methyl-2-vinyl-1-benzothien-5-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 365A andExample 77B for Example 1B and Example 1C, respectively, in Example 1D.MS (ESI(−)) m/e 628 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ2.49 (s, 3H),3.29 (t, 2H), 3.69 (dt, 2H), 5.39 (d, 1H), 5.61 (d, 1H), 7.19 (m, 2H),7.28 (dd, 2H), 7.38 (d, 2H), 7.74(dd, 1H), 7.90-8.08 (m, 8H), 8.53 (d,1H), 8.80 (dd, 1H).

EXAMPLE 3664-(4-((((3-nitro-4-((2-(phenylthio)ethyl)amino)phenyl)sulfonyl)amino)carbonyl)phenyl)-N-(2-phenylethyl)piperazine-1-carboxamide

A solution of Example 173A (54.1 mg, 0.1 mmol) in NMP (2 mL) at roomtemperature was treated with phenethylisocyanate (0.2 mmol), stirred for18 hours, diluted with water, and centrifuged. The solid was purified byflash column chromatography on silica gel with 0-5%methanol/dichloromethane to provide the desired product. MS (ESI(−)) m/e687 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ8.75 (t, 1H), 8.58 (d, 1H), 7.90(dd, 1H), 7.75 (d, 2H), 7.39-7.34 (m, 2H), 7.31-7.14 (m, 9H), 6.94 (d,2H), 6.71 (t, 1H), 3.66 (q, 2H), 3.42-3.39 (m, 4H), 3.30-3.21 (m, 8H),2.72 (dd, 2H).

EXAMPLE 367N-(4-(2-(3-morpholin-4-yl-3-oxopropyl)-1,3-benzothiazol-5-yl)benzoyl)-3-nitro-4-((2(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting morpholine forpiperidine in Example 320. MS (ESI) m/e 730, 732 (M−H)⁻, (M+H)⁺; ¹H NMR(300 MHz, DMSO-d₆) δ2.95 (t, 3H), 3.27 (t, 2H), 3.36 (t, 2H), 3.42-3.65(m, 10H), 6.99 (d, 1H), 7.22 (tt, 1H), 7.32 (td, 2H), 7.40 (dd, 2H),7.72 (d, 2H), 7.74 (dd, 1H), 7.88 (dd, 1H), 7.98 (d, 2H), 8.10 (d, 1H),8.18 (d, 1H), 8.52 (d, 1H), 8.52 (t, 1H).

EXAMPLE 3683-nitro-N-(4-(1-pentyl-1H-pyrazol-4-yl)benzoyl)-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 322B andExample 77B for Example 1B and Example 1C, respectively, in Example 1D.MS (ESI(−)) m/e 592 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ0.85 (t, 3H),1.25 (m, 4H), 1.80 (tt, 2H), 3.27 (t, 2H), 3.61 (dt, 2H), 4.09 (t, 2H),7.00 (d, 1H), 7.20 (t, 1H), 7.30 (t, 2H), 7.40 (d, 2H), 7.51 (d, 2H),7.87 (m, 4H), 8.21 (s, 1H), 8.51 (d, 1H), 8.54 (t, 1H).

EXAMPLE 369N-(4-(1-benzyl-1H-pyrrol-3-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamideEXAMPLE 369A 1-benzyl-2,5-dihydro-1H-pyrrol-3-yl trifluoroacetate

The desired product was prepared by substituting1-benzyl-3-pyrrolidinone for 4-tert-butylcyclohexanone in Example 5A.

EXAMPLE 369B methyl 4-(1-benzyl-1H-pyrrol-3-yl)benzoate

The desired product was prepared by substituting Example 369A forExample 5A in Example 5B. MS (DCI (+)) m/e 292 (M+H)⁺.

EXAMPLE 369CN-(4-(1-benzyl-1H-pyrrol-3-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 369B forExample 230B in Example 230C. MS (ESI(−)) m/e 611 (M−H)⁻; ¹H NMR (300MHz, DMSO-d₆) δ8.78 (br t, 1H), 8.62 (d, 1H), 7.92 (dd, 1H), 7.80 (d,2H), 7.60 (d, 2H), 7.50 (t, 1H), 7.40-7.15 (m, 11H), 6.92 (t, 1H), 6.55(t, 1H), 5.10 (s, 2H), 3.65 (m, 2H), 3.35 (m, 2H).

EXAMPLE 370(3R)-N-(tert-butyl)-3-((4-((((4′-fluoro-1,1′-biphenyl-4-yl)carbonyl)amino)sulfonyl)-2-nitrophenyl)amino)-4-(phenylthio)butanamideEXAMPLE 370A(3R)-3-((4-(aminosulfonyl)-2-nitrophenyl)amino)-N-(tert-butyl)-4-(phenylthio)butanamide

The desired product was prepared by substituting tert-butylamine fordimethylamine in Example 122F.

EXAMPLE 370B(3R)-N-(tert-butyl)-3-((4-((((4′-fluoro-1,1′-biphenyl-4-yl)carbonyl)amino)sulfonyl)-2-nitrophenyl)amino)-4-(phenylthio)butanamide

The desired product was prepared by substituting Example 370A forExample 1C in Example 1D. MS (ESI(−)) m/e 663 (M−H)⁻; ¹H NMR (500 MHz,methanol-d₄) δ8.73 (d, 1H), 8.09 (d, 1H), 7.93 (dd, 1H), 7.67 (m, 4H),7.32 (m, 2H), 7.20-7.10 (m, 4H), 6.97 (d, 1H), 4.40 (m, 1H), 3.36 (dd,1H), 3.22 (dd, 1H), 2.62 (m, 2H), 1.22 (s, 9H).

EXAMPLE 3714-((2-(((tert-butylamino)carbonyl)amino)-1-((phenylthio)methyl)ethyl)amino)-N-((4′-fluoro-1,1′-biphenyl-4-yl)carbonyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting tert-butyl isocyanatefor acetyl chloride in Example 310. MS (ESI(−)) m/e 678 (M−H)⁻; ¹H NMR(400 MHz, methanol-d₄) δ8.76 (d, 1H), 7.93 (m, 3H), 7.72 (d, 1H), 7.69(m, 2H), 7.31 (m, 2H), 7.22-7.10 (m, 5H), 7.04 (d, 1H), 4.16 (m, 1H),3.38 (m, 2H), 3.17 (dd, 1H), 1.21 (s, 9H), and the remaining proton isburied under solvent peaks.

EXAMPLE 3723-nitro-4-((2-(phenylthio)ethyl)amino)-N-(4-((1S,4R)-1,7,7-trimethylbicyclo(2.2.1)hept-2-yl)benzoyl)benzenesulfonamideEXAMPLE 372A (1R,4R)-1,7,7-trimethylbicyclo(2.2.1)hept-2-en-2-yltrifluoroacetate

The desired product was prepared by substituting camphor for4-tert-butylcyclohexanone in Example 5A.

EXAMPLE 372B methyl4-((1R,4R)-1,7,7-trimethylbicyclo(2.2.1)hept-2-en-2-yl)benzoate

The desired product was prepared by substituting Example 372A forExample 5A in Example 5B. MS (DCI (+)) m/e 243 (M+H)⁺.

EXAMPLE 372C methyl4-((1S,4R)-1,7,7-trimethylbicyclo(2.2.1)hept-2-yl)benzoate

A mixture of Example 372B (100 mg) and 10% Pd/C (20 mg) in ethyl acetate(5 mL) and ethanol (5 mL) at room temperature was stirred under H₂ for18 hours, filtered, and concentrated to provide the desired product. MS(DCI(+)) m/e 245 (M+H)⁺.

EXAMPLE 372D3-nitro-4-((2-(phenylthio)ethyl)amino)-N-(4-((1S,4R)-1,7,7-trimethylbicyclo(2.2.1)hept-2-yl)benzoyl)benzenesulfonamide

The desired product was prepared by substituting Example 372C forExample 230B in Example 230C. MS (ESI(−)) m/e 592 (M−H)⁻; ¹H NMR (300MHz, DMSO-d₆) δ8.78 (br t, 1H), 8.60 (d, 1H), 7.92 (dd, 1H), 7.85 (d,2H), 7.40-7.15 (m, 8H), 3.70 (m, 4H), 3.00(m, 1H), 2.30 (m, 1H),1.95-1.10 (m, 6H), 1.00-0.70 (6s, 9H).

EXAMPLE 373 isopropyl4-(4-((((3-nitro-4-((2-(phenylthio)ethyl)amino)phenyl)sulfonyl)amino)carbonyl)phenyl)piperazine-1-carboxylate

The desired product was prepared by substituting isopropyl chloroformatefor 2-methoxyethyl chloroformate in Example 325. MS (ESI(−)) m/e 626(M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ8.74 (t, 1H), 8.58 (d, 1H), 7.90 (dd,1H), 7.76 (d, 2H), 7.39-7.35 (m, 2H), 7.29-7.23 (m, 2H), 7.20-7.14 (m,2H), 6.93 (d, 2H), 4.79 (hept, 2H), 4.06 (q, 2H), 3.66 (q, 2H),3.50-3.44 (m, 4H), 3.32-3.23 (m, 6H), 1.20 (d, 6H).

EXAMPLE 374N-(4-(2-cyanoquinolin-8-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamideEXAMPLE 374A 2-cyanoquinolin-8-yl trifluoroacetate

The desired product was prepared by substituting2-cyano-8-hydroxyquinoline for vanillin in Example 122H.

EXAMPLE 374BN-(4-(2-cyanoquinolin-8-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 374A forExample 389A in Example 389B. MS (ESI(−)) m/e 626 (M−H)⁻; ¹H NMR (400MHz, methanol-d₄) δ8.81 (d, 1H), 8.52 (d, 1H), 8.18 (d, 1H), 8.05 (m,2H), 7.97-7.87 (m, 6H), 7.79 (m, 1H), 7.38 (m, 2H), 7.22 (tt, 2H), 7.17(tt, 1H), 7.07 (d, 1H), 3.70 (q, 2H), 3.28 (t, 2H).

EXAMPLE 3753-nitro-4-((2-(phenylthio)ethyl)amino)-N-(4-(1-(pyridin-4-ylmethyl)-1,2,3,6-tetrahydropyridin-4-yl)benzoyl)benzenesulfonamide

The desired product was prepared by substituting4-pyridinecarboxaldehyde for 3-pyridinecarboxaldehyde in Example 340B.MS (ESI(−)) m/e 628 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ8.78 (br t, 1H),8.70 (d, 1H), 8.70 (dd, 1H), 8.60 (d, 1H), 8.05 (m, 1H), 7.95 (d, 2H),7.62 (d, 2H), 7.60 (dd, 1H), 7.40-7.15 (m, 6H), 6.35 (m, 1H), 4.52 (d,2H), 3.92 (m, 4H), 3.45 (t, 4H), 2.82 (m, 2H).

EXAMPLE 3763-nitro-4-((2-(phenylthio)ethyl)amino)-N-(4-(1-(pyridin-2-ylmethyl)-1,2,3,6-tetrahydropyridin-4-yl)benzoyl)benzenesulfonamide

The desired product was prepared by substituting2-pyridinecarboxaldehyde for 3-pyridinecarboxaldehyde in Example 340B.MS (ESI(−)) m/e 628 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ8.78 (br t, 1H),8.70 (dd, 1H), 8.62 (d, 1H), 7.95 (dd, 1H), 7.92 (t, 1H), 7.90 (d, 2H),7.62 (d, 2H), 7.58 (d, 1H), 7.50 (m, 1H), 7.40-7.15 (m, 6H), 6.35 (m,1H), 4.52 (d, 2H), 3.92 (m, 2H), 3.65 (m, 2H), 3.55-3.35 (m 4H), 2.82(m, 2H).

EXAMPLE 377 ethyl4-(5-(4-((((3-nitro-4-((2-(phenylthio)ethyl)amino)phenyl)sulfonyl)amino)carbonyl)phenyl)-1,3-benzothiazol-2-yl)butanoate

The desired product was prepared by substituting ethyl 3-bromopropionatefor allyl bromide in Example 213. MS (ESI) m/e 703, 705 (M−H)⁻, (M+H)⁺;¹H NMR (300 MHz, DMSO-d₆) δ1.19 (t, 3H), 2.08 (tt, 2H), 2.47 (t, 2H),3.17 (t, 2H), 3.27 (t, 2H), 3.64 (dt, 2H), 4.07 (q, 2H), 7.09 (d, 1H),7.18 (tt, 1H), 7.29 (td, 2H), 7.39 (d, 2H), 7.76 (d, 1H), 7.80 (d, 2H),7.93 (dd, 1H), 7.98 (d, 2H), 8.18 (d, 1H), 8.27 (d, 1H), 8.57 (d, 1H),8.64 (t, 1H).

EXAMPLE 378N˜2˜(tert-butoxycarbonyl)-N˜1˜-(1-(N-(tert-butoxycarbonyl)leucyl)-4-(4-((((3-nitro-4-((2-(phenylthio)ethyl)amino)phenyl)sulfonyl)amino)carbonyl)phenyl)-1,2,3,6-tetrahydropyridin-2-yl)-N˜1˜-(1-(N-(tert-butoxycarbonyl)leucyl)-4-(4-((((3-nitro-4-((2-(phenylthio)ethyl)amino)phenyl)sulfonyl)amino)carbonyl)phenyl)-1,2,5,6-tetrahydropyridin-2-yl)leucinamide

A mixture of Example 340A (150 mg, 0.25 mmol), BOC-leucine (70 mg, 0.3mmol), EDCI (77 mg, 0.40 mmol), HOBT (55 mg, 0.40 mmol), anddiisopropylethylamine (0.2 mL) in THF (0.5 mL) at room temperature wasstirred for 16 hours, diluted with ethyl acetate (50 mL), washedsequentially with 1N HCl (5 mL), water (30 mL) and brine (30 mL), dried(MgSO₄), filtered, and concentrated. The concentrate was purified byflash column chromatography on silica gel with 5%methanol/dichloromethane to provide the desired product. MS (ESI(−)) m/e750 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ8.72 (br t, 1H), 8.60 (d, 1H),7.92 (dd, 1H), 7.85 (d, 2H), 7.50 (br d, 1H), 7.55 (d, 2H), 7.40-7.15(m, 6H), 6.35 (m, 1H), 4.50 (m, 1H), 4.18 (d, 2H), 3.65 (m, 4H),3.40-3.25 (m, 4H), 1.65 (m, 1H), 1.35 (s, 9H), 0.95 (d, 6H).

EXAMPLE 3793-methyl-5-(4-((((3-nitro-4-((2-(phenylthio)ethyl)amino)phenyl)sulfonyl)amino)carbonyl)phenyl)-1-benzothiophene-2-carboxamide

A solution of Example 401D (100 mg, 0.16 mmol) in tert-butyl alcohol (5mL) and water (0.5 mL) at room temperature was treated with KOH (500 mg,8.90 mmol) and 18-crown-6 (400 mg, 1.51 mmol), heated to 100° C. for 90minutes, treated with 1M HCl (20 mL), and extracted with 10%methanol/ethyl acetate (3×50 mL). The combined extracts were washed withbrine (10 mL), dried (Na₂SO₄), filtered, and concentrated. Theconcentrate was purified by flash column chromatography on silica gelwith 5-15% methanol/ethyl acetate to provide the desired product. MS(ESI) m/e 645, 647 (M−H)⁻, (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ1.90 (s,3H), 3.27 (t, 2H), 3.62 (dt, 2H), 6.98 (d, 1H), 7.20 (tt, 1H), 7.31 (td,2H), 7.40 (dd, 1H), 7.68 (s, 2H), 7.74 (d, 2H), 7.80 (dd, 1H), 7.90 (dd,1H), 7.99 (d, 2H), 8.04 (d, 1H), 8.14 (d, 1H), 8.50 (t, 1H), 8.52 (d,1H).

EXAMPLE 380N-(4-((((4′-fluoro-1,1′-biphenyl-4-yl)carbonyl)amino)sulfonyl)-2-nitrophenyl)adamantane-1-carboxamideEXAMPLE 380A4-amino-N-((4′-fluoro-1,1′-biphenyl-4-yl)carbonyl)-3-nitrobenzenesulfonamide

A solution of Example 1D (1.0 g) in methanol (10 mL) and concentratedaqueous ammonia (3 mL) was heated in a sealed pressure tube to 60° C.for 16 hours, cooled to 0° C., diluted with ethyl acetate (100 mL),washed with water (30 mL) and brine (10 mL), dried (MgSO₄), filtered,and concentrated to provide the desired product.

EXAMPLE 380BN-(4-((((4′-fluoro-1,1′-biphenyl-4-yl)carbonyl)amino)sulfonyl)-2-nitrophenyl)adamantane-1-carboxamide

A solution of Example 380A (101 mg, 0.25 mmol) in THF (3 mL) was treatedwith 60% sodium hydride in oil (40 mg, 1.0 mmol), stirred for 30minutes, treated with 1-adamantanecarbonyl chloride (60 mg, 0.30 mmol),stirred for 30 minutes, adjusted to pH<7 with 4M HCl in dioxane (0.5mL), filtered, and concentrated. The concentrate was purified by flashcolumn chromatography on silica gel with 30-100% ethyl acetate/hexanesto provide the desired product. MS (ESI(−)) m/e 576 (M−H)⁻; ¹H NMR (300MHz, DMSO-d₆) δ10.23 (s, 1H), 8.52 (d, 1H), 8.23 (dd, 1H), 8.19 (d, 1H),7.95 (d, 2 H, 7.75 (m, 4H), 7.31 (tt, 2H), 2.05 (3s, 3H), 1.90 (m, 6H),1.70 (m, 6H).

EXAMPLE 381N-(4-(2-hexyl-1,3-benzothiazol-5-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting 1-iodopentane for allylbromide in Example 213. MS (ESI) m/e 673, 675 (M−H)⁻, (M+H)⁺; ¹H NMR(300 MHz, DMSO-d₆) δ0.87 (t, 3H), 1.17-1.44 (m, 6H), 1.82 (tt, 2H), 3.12(t, 2H), 3.27 (t, 2H), 3.62 (dt, 2H), 7.02 (d, 1H), 7.19 (tt, 1H), 7.31(t, 2H), 7.39 (d, 2H), 7.73 (d, 2H), 7.74 (d, 1H), 7.89 (dd, 1H), 7.98(d, 2H), 8.12 (d, 1H), 8.22 (d, 1H), 8.53 (d, 1H), 8.55 (t, 1H).

EXAMPLE 382N-((3,4′-difluoro-1,1′-biphenyl-4-yl)carbonyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamideEXAMPLE 382A methyl 4-chloro-2-fluorobenzoate

The desired product was prepared by substituting3-chloro-2-fluorobenzoic acid for 4-bromo-3-fluorobenzoic acid inExample 311A.

EXAMPLE 382B methyl 3,4′-difluoro-1,1′-biphenyl-4-carboxylate

The desired product was prepared by substituting Example 382A and4-fluorophenylboronic acid for 5-chloro-2-methyl-1,3-benzoxazole and4-(methoxycarbonyl)phenylboronic acid in Example 54A.

EXAMPLE 382CN-((3,4′-difluoro-1,1′-biphenyl-4-yl)carbonyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 382B andExample 77B for Example 5C and Example 3A, respectively, in Example 5D.MS (ESI(−)) m/e 568 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ8.64 (t, 1H),8.54 (d, 1H), 7.88 (dd, 1H), 7.78 (m, 2H), 7.70 (t, 1H), 7.49 (m, 2H),7.39 (m, 2H), 7.30 (m, 4H)-7.20 (tt, 1H), 7.10 (d, 1H), 3.66 (q, 2H),3.20 (t, 2H).

EXAMPLE 383N-((2′-methoxy-4′-(2-morpholin-4-yl-2-oxoethyl)-1,1′-biphenyl-4-yl)carbonyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamideEXAMPLE 383A methyl2′-methoxy-4′-(2-morpholin-4-yl-2-oxoethyl)-1,1′-biphenyl-4-carboxylate

The desired product was prepared by substituting morpholine for1-methylpiperazine in Example 328B.

EXAMPLE 383BN-((2′-methoxy-4′-(2-morpholin-4-yl-2-oxoethyl)-1,1′-biphenyl-4-yl)carbonyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 383A andExample 77B for Example 5C and Example 3A, respectively, in Example 5D.MS (ESI(−)) m/e 689 (M−H)⁻; ¹H NMR (500 MHz, DMSO-d₆) δ8.77 (t, 1H),8.62 (d, 1H), 7.93 (dd, 1H), 7.88 (d, 2H), 7.57 (d, 2H), 7.37 (m, 2H),7.26 (m, 3H), 7.18 (m, 2H), 6.99 (d, 1H), 6.89 (dd, 1H), 3.76 (s, 2H),3.75 (s, 3H), 3.67 (q, 2H), 3.56-3.52 (m, 6H), 3.47 (m, 2H), 3.26 (d,2H).

EXAMPLE 3844-((4-azido-1-((phenylthio)methyl)butyl)amino)-N-((4′-fluoro-1,1′-biphenyl-4-yl)carbonyl)-3-nitrobenzenesulfonamideEXAMPLE 384A methyl(2E)-4-((tert-butoxycarbonyl)amino)-5-(phenylthio)pent-2-enoate

A solution of Example 175A (798 mg, 2.56 mmol) in toluene at −78° C. wastreated with 1M DIBAL-H in toluene (3.1 mL), stirred for 2 hours, pouredinto a mixture of 1M HCl (5 mL) and ice (˜15 g), and extracted withethyl acetate (100 mL). The extract was washed with 0.1M HCl (20 mL) andbrine (10 mL), dried (MgSO₄), filtered, and concentrated.

The concentrate was treated with methyl(triphenylphospharanylidene)acetate (1.35 g, 4.0 mmol).and THF (10 mL),stirred at room temperature for 16 hours, diluted with hexanes (20 mL),and filtered through silica gel (20 g). The silica gel pad was rinsedwith 1:1 ethyl acetate/hexanes and the combined organic phases wereconcentrated. The concentrate was purified by flash columnchromatography on silica gel with 10-20% ethyl acetate/hexanes toprovide the desired product.

EXAMPLE 384B methyl4-((tert-butoxycarbonyl)amino)-5-(phenylthio)pentanoate

A mixture of Example 384A (650 mg, 1.92 mmol) and 10% Pd/C (2.3 g, 2.2mmol) in ethyl acetate (15 mL0 and methanol (5 mL) was stirred at roomtemperature under a hydrogen balloon for 6 hours and filtered throughdiatomaceous earth (Celite®). The pad was rinsed with hot ethyl acetate,and the combined organic phases were concentrated to provide the desiredproduct.

EXAMPLE 384C tert-butyl 4-hydroxy-1-((phenylthio)methyl)butylcarbamate

A solution of Example 384B (538 mg, 1.6 mmol) in THF (4 mL) at −50° C.was treated with 1M lithium triethylborohydride in THF (4 mL), stirredfor 1 hour, poured into ice (˜15 g), and extracted with ethyl acetate(100 mL). The extract was washed with water (20 mL) and brine (10 mL),dried (MgSO₄), filtered, and concentrated to provide the desired productof sufficient purity for subsequent use.

EXAMPLE 384D tert-butyl 4-azido-1-((phenylthio)methyl)butylcarbamate

The desired product was prepared by substituting Example 384C forExample 434B in Example 434C.

EXAMPLE 384E4-((4-azido-1-((phenylthio)methyl)butyl)amino)-N-((4′-fluoro-1,1′-biphenyl-4-yl)carbonyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 384D forExample 175B in Example 175D. MS (ESI(−)) m/e 607 (M−H)⁻; ¹H NMR (300MHz, DMSO-d₆) δ8.57 (d, 1H), 8.33 (d, 1H), 7.98 (d, 2H), 7.87 (dd, 1H),7.70 (m, 4H), 7.32 (m, 2H), 7.24 (m, 2H), 7.13 (m, 4H), 4.15 (m, 1H),3.38 (m, 2H), 2.51 (m, 2H), 1.81 m, 2H), 1.60 (m, 2H).

EXAMPLE 385N-butyl-3-(5-(4-((((3-nitro-4-((2-(phenylthio)ethyl)amino)phenyl)sulfonyl)amino)carbonyl)phenyl)-1,3-benzothiazol-2-yl)propanamide

The desired product was prepared by substituting Example 330A andExample 77B for Example 1B and Example 1C, respectively, in Example 1D.MS (ESI) m/e 716, 718 (M−H)⁻, (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ0.83(t, 3H), 1.24 (m, 2H), 1.35 (m, 2H), 2.66 (t, 2H), 3.05 (tt, 2H), 3.28(t, 2H), 3.30 (t, 2H), 3.61 (dt, 2H), 7.01 (d, 1H), 7.20 (tt, 1H), 7.31(td, 2H), 7.40 (dd, 2H), 7.72 (d, 2H), 7.74 (dd, 1H), 7.88 (dd, 1H),7.92 (t, 1H), 7.98 (d, 2H), 8.11 (d, 1H), 8.12 (dd, 1H), 8.52 (d, 1H),8.54 (t, 1H).

EXAMPLE 3863-nitro-4-((2-(phenylthio)ethyl)amino)-N-(4-(4-(2-propylpentanoyl)piperazin-1-yl)benzoyl)benzenesulfonamide

The desired product was prepared by substituting dipropylacetyl chloridefor 2-methoxyethyl chloroformate in Example 325. MS (ESI(−)) m/e 666(M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ8.77 (t, 1H), 8.60 (d, 1H), 7.91 (dd,1H), 7.76 (d, 2H), 7.39-7.35 (m, 2H), 7.29-7.14 (m, 4H), 6.95 (d, 2H),4.79 (hept, 2H), 3.70-3.60 (m, 6H), 3.32-3.23 (m, 6H), 2.82-2.73 (m,1H), 1.56-1.43 (m, 2H), 1.34-1.16 (m, 4H), 0.83 (t, 6H).

EXAMPLE 387N-(4-(1-butyl-2-(2-methoxyethyl)-1H-benzimidazol-5-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamideEXAMPLE 387A 5-bromo-1-butyl-2-(2-methoxyethyl)-1H-benzimidazole

The desired product was prepared by substituting Example 166B and3-methoxypropionic acid for Example 343A and valeric acid, respectively,in Example 343B.

EXAMPLE 387BN-(4-(1-butyl-2-(2-methoxyethyl)-1H-benzimidazol-5-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 387A andExample 214D for 6-bromoindole and 4-(dihydroxyboryl)benzoic acid,respectively, in Example 4A. MS (ESI) m/e 686, 688 (M−H)⁻, (M+H)⁺; ¹HNMR (300 MHz, DMSO-d₆) δ0.92 (t, 3H), 1.35 (qt, 2H), 1.72 (tt, 2H), 2.12(t, 2H), 3.26 (t, 2H), 3.28 (s, 3H), 3.61 (dt, 2H), 3.84 (t, 2H), 4.23(t, 2H), 6.99 (d, 1H), 7.21 (tt, 1H), 7.32 (td, 2H), 7.40 (d, 2H),7.46-7.68 (m, 4H), 7.89 (dd, 1H), 7.93-7.98 (m, 3H), 8.52 (d, 1H), 8.53(t, 1H).

EXAMPLE 388N-(4-((1S,4R)-bicyclo(2.2.1)hept-2-en-2-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamideEXAMPLE 388A (1S,4R)-bicyclo(2.2.1)hept-2-en-2-yl trifluoroacetate

The desired product was prepared by substituting norcamphor for4-tert-butylcyclohexanone in Example 5A.

EXAMPLE 388B methyl 4-((1S,4R)-bicyclo(2.2.1)hept-2-en-2-yl)benzoate

The desired product was prepared by substituting Example 388A forExample 5A in Example 5B. MS (DCI(+)) m/e 229 (M+H)⁺.

EXAMPLE 388CN-(4-((1S,4R)-bicyclo(2.2.1.)hept-2-en-2-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 388B forExample 230B in Example 230C. MS (ESI(−)) m/e 548 (M−H)⁻; ¹H NMR (300MHz, DMSO-d₆) δ8.78 (br t, 1H), 8.60 (d, 1H), 7.92 (dd, 1H), 7.85 (d,2H), 7.50 (d, 2H), 7.40-7.15 (m, 6H), 6.60 (d, 1H), 3.70 (m, 2H), 3.40(m, 1H), 3.00 (m, 1H), 1.75 (m, 2H), 1.45 (m, 2H), 1.25 (m, 2H), 1.05(m, 2H).

EXAMPLE 389N-(4-(5-fluoroquinolin-8-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamideEXAMPLE 389A 5-fluoroquinolin-8-yl trifluoroacetate

The desired product was prepared by substituting5-fluoro-8-hydroxyquinoline for vanillin in Example 122H.

EXAMPLE 389BN-(4-(5-fluoroquinolin-8-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

A mixture of Example 108A (176 mg, 0.30 mmol), Example 389A (180 mg,0.60 mmol), Pd₂dba₃ (27 mg, .0.03 mmol), triphenylarsine (37 mg, 0.12mmol) and 1M Na₂CO₃ (3 mL) in 1,4-dioxane (6 mL) was heated to 90° C.for 16 hours, cooled to room temperature, diluted with ethyl acetate(200 mL), washed with water (100 mL) and brine (50 mL), dried (MgSO₄),filtered, and concentrated. The concentrate was purified by flash columnchromatography on silica gel with 1:1 ethyl acetate/dichloromethane toprovide the desired product. MS (ESI(−)) m/e 601 (M−H)⁻; ¹H NMR (300MHz, DMSO-d₆) δ8.99 (dd, 1H), 8.74 (br t, 1H), 8.62 (d, 1H), 8.57 (dd,1H), 7.95 (m, 4H), 7.82 (dd, 1H), 7.70 (m, 3H), 7.55 (dd, 1H), 7.48 (d,2H), 7.28 (t, 2H), 7.19 (m, 2H), 3.67 (q, 2H), 3.28 (t, 2H).

EXAMPLE 390N˜2˜-(4-((((4′-fluoro-1,1′-biphenyl-4-yl)carbonyl)amino)sulfonyl)-2-nitrophenyl)-S-phenylcysteinamideEXAMPLE 390A N²-tert-butoxycarbonyl-S-phenylcysteinamide

The desired product was prepared by substituting 0.5M ammonia in dioxanefor morpholine in Example 180A.

EXAMPLE 390BN˜2˜-(4-((((4′-fluoro-1,1′-biphenyl-4-yl)carbonyl)amino)sulfonyl)-2-nitrophenyl)-S-phenylcysteinamide

The desired product was prepared by substituting Example 390A forExample 175B in Example 175D. MS (ESI(−)) m/e 593 (M−H)⁻; ¹H NMR (300MHz, DMSO-d₆) δ8.49 (d, 1H), 7.96 (d, 2H), 7.89 (dd, 1H), 7.75 (m, 3H),7.60 (d, 2H), 7.45 (1H), 7.32-7.13 (m, 7H), 4.52 (m, 1H), 3.60 (m, 1H),2.45 (m, 1H).

EXAMPLE 391N-(4-(2-aminoquinolin-8-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 355A forExample 389A in Example 389B. MS (ESI(−)) m/e 598 (M−H)⁻; ¹H NMR (400MHz, DMSO-d₆) δ8.67 (t, 1H), 8.58 (d, 1H), 7.95 (m, 5H), 7.80-7.45 (m,6H), 7.39 (m, 2H), 7.30 (t, 2H), 7.20 (tt, 1H), 3.65 (q, 2H), 3.28 (t,2H).

EXAMPLE 3923-nitro-4-((2-(phenylthio)ethyl)amino)-N-(4-(1-(pyridin-3-ylcarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)benzoyl)benzenesulfonamide

The desired product was prepared by substituting nicotinoyl chloride for4-morpholinecarbonyl chloride in Example 317. MS (ESI(−)) m/e 642(M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ8.80 (br t, 1H), 8.70 (d, 2H), 8.62(d, 1H), 7.92(m,2H), 7.89 (d, 2H), 7.58 (d, 2H), 7.55 (m, 1H), 7.40-7.15(m, 6H), 6.45 and 6.25 (2m, 1H), 4.32 and 4.12 (2d, 2H), 3.92 (m, 2H),3.65 (m, 2H), 3.25 (t,2H), 2.62 (m, 2H).

EXAMPLE 3934-((3-tert-butoxy-2-(phenylthio)propyl)amino)-N-((4′-fluoro-1,1′-biphenyl-4-yl)carbonyl)-3-nitrobenzenesulfonamideand4-((2-tert-butoxy-1-((phenylthio)methyl)ethyl)amino)-N-((4′-fluoro-1,1′-biphenyl-4-yl)carbonyl)-3-nitrobenzenesulfonamideEXAMPLE 393A 3-tert-butoxy-2-(phenylthio)propan-1-ol and1-tert-butoxy-3-(phenylthio)propan-2-ol

The desired products were prepared by substituting tert-butyl glycidylether for cyclohexene oxide in Example 7A.

EXAMPLE 393B ((2-azido-1-(tert-butoxymethyl)ethyl)thio)benzene and((2-azido-3-tert-butoxypropyl)thio)benzene

The desired product was prepared by substituting Example 393A forExample 7A in Example 7B.

EXAMPLE 393C4-((3-tert-butoxy-2-(phenylthio)propyl)amino)-3-nitrobenzenesulfonamideand4-((2-tert-butoxy-1-((phenylthio)methyl)ethyl)amino)-3-nitrobenzenesulfonamide

A mixture of Example 393B (877 mg, 3.03 mmol), triphenylphosphine (1.58g, 6.0 mmol), and water (0.18 mL, 10 mmol) in THF (95 mL) at roomtemperature was stirred for 18 hours and concentrated. The concentratewas treated with Example 122C (801 mg, 3.64 mmol),N,N-diisopropylethylamine (1.0 mL), and 1,4-dioxane (5 mL), heated to60° C. for 16 hours, diluted with ethyl acetate (100 mL), washed withwater (45 mL) and brine (10 mL), dried (MgSO₄), filtered, andconcentrated. The concentrate was purified by flash columnchromatography on silica gel with 10-30% ethyl acetate/dichloromethaneto provide the desired products as a 1.5:1 mixture. MS (ESI(+)) m/e 440(M+H)⁺.

EXAMPLE 393D4-((3-tert-butoxy-2-(phenylthio)propyl)amino)-N-((4′-fluoro-1,1′-biphenyl-4-yl)carbonyl)-3-nitrobenzenesulfonamideand4-((2-tert-butoxy-1-((phenylthio)methyl)ethyl)amino)-N-((4-fluoro-1,1′-biphenyl-4-yl)carbonyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 393C forExample 1C in Example 1D. MS (ESI(−)) m/e 636 (M−H)⁻; ¹H NMR (300 MHz,DMSO-d₆), 2:1 mixture of isomers δ8.84 (br t, 2/3H), 8.68 (br d, 1/3H),8.62, 8.61 (2d, 1H), 7.96 (2d, 2H), 7.92, 7.89 (2dd, 1H), 7.78 (m, 4H),7.45-7.10 (m, 8H), 4.14 (m, 2/3H), 3.80-3.50 (m, 4H), 1.12, 1.11 (2s,9H).

EXAMPLE 394N-(4-(1-(cyclohexylmethyl)-1H-pyrazol-4-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamideEXAMPLE 394A 1-(cyclohexylmethyl)-4-iodo-1H-pyrazole

The desired product was prepared by substituting(bromomethyl)cyclohexane for 1-bromooctane in Example 198A. MS (ESI(+))m/e 291 (M+H)⁺.

EXAMPLE 394B 4-(1-(cyclohexylmethyl)-1H-pyrazol-4-yl)benzoic acid

The desired product was prepared by substituting Example 394A for6-bromoindole in Example 4. MS (ESI(−)) m/e 283 (M−H)⁻.

EXAMPLE 394CN-(4-(1-(cyclohexylmethyl)-1H-pyrazol-4-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 394B andExample 77B for Example 1B and Example 1C, respectively, in Example 1D.MS (ESI(−)) m/e 618 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ0.95 (m, 2H),1.18 (m, 4H), 1.52 (m, 2H), 1.63 (m, 2H), 1.81 (m, 1H), 3.27 (t, 2H),3.60 (dt, 2H), 3.92 (d, 2H), 6.99 (d, 1H), 7.19 (t, 1H), 7.30 (t, 2H),7.40 (d, 2H), 7.51 (d, 2H), 7.87 (m, 4H), 8.18 (s, 1H), 8.51 (d, 1H),8.54 (t, 1H).

EXAMPLE 395N-(4-(6-methoxypyridin-3-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting5-bromo-2-methoxypyridine for 2,8-bistrifluoromethyl-3-chloroquinolinein Example 319. MS (ESI) m/e 565, 563 (M+H)⁺, (M−H)⁻; ¹H NMR (500 MHz,DMSO-d₆) δ8.78 (t,H), 8.63 (d, 1H), 8.57 (d, 1H), 8.09 (dd, 1H),7.97-7.93 (m, 3H), 7.81 (d, 2H), 7.37 (dt, 2H), 7.27 (td, 2H), 7.22 (d,1H), 7.17 (tt, 1H), 6.93 (d, 1H), 3.91 (s, 3H), 3.68 (q, 2H), 3.29 (t,2H).

EXAMPLE 396N-((2′-methoxy-4′-(2-morpholin-4-ylethyl-1,1′-biphenyl-4-yl)carbonyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamideEXAMPLE 396A methyl2′-methoxy-4′-(2-morpholin-4-ylethyl)-1,1′-biphenyl-4-carboxylate

The desired product was prepared by substituting Example 383A forExample 122F in Example 122G.

EXAMPLE 396BN-((2′-methoxy-4′-(2-morpholin-4-ylethyl)-1,1′-biphenyl-4-yl)carbonyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 396A andExample 77B for Example 5C and Example 3A, respectively, in Example 5D.MS (ESI(−)) m/e 675 (M−H)⁻; ¹H NMR (500 MHz, DMSO-d₆) δ10.3-10.1 (br s,1H), 8.78 (t, 1H), 8.64 (d, 1 H), 7.94 (dd, 1H), 7.90 (d, 2H), 7.57 (d,2H), 7.37 (m, 2H), 7.36-7.18 (m, 5H), 7.06 (d, 1H), 6.97 (dd, 1H), 4.00(m, 2H), 3.78 (s, 3H), 3.67 (q, 2H), 3.42 (m, 2H), 3.29 (t, 2H), 3.15(m, 2H), 3.05 (m, 2H), remaining 2 protons are buried under water peak(3.8-3.4 ppm).

EXAMPLE 397N-((2′-methoxy-4′-(3-morpholin-4-yl-3-oxopropyl)-1,1′-biphenyl-4-yl)carbonyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 122M andExample 77B for Example 5C and Example 3A, respectively, in Example 5D.MS (ESI(−)) m/e 703 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ8.79 (t, 1H),8.63 (d, 1H), 7.94 (dd, 1H), 7.88 (d, 2H), 7.57 (d, 2H), 7.37 (m, 2H),7.30-7.14 (m, 5H), 7.02 (d, 1H), 6.92 (dd, 1H), 3.76 (s, 3H), 3.67 (q,2H), 3.53 (m, 4H), 3.44 (m, 4H), 3.28 (d, 2H), 2.85 (t, 2), 2.66 (t,2H).

EXAMPLE 398N-(2-hydroxyethyl)-3-methyl-5-(4-((((3-nitro-4-((2-(phenylthio)ethyl)amino)phenyl)sulfonyl)amino)carbonyl)phenyl)-1-benzothiophene-2-sulfonamideEXAMPLE 398A5-chloro-N-(2-hydroxyethyl)-3-methyl-1-benzothiophene-2-sulfonamide

The desired product was prepared by substituting2-chlorosulfonyl-5-chloro-3-methylbenzothiophene and ethanolamine fordimethylcarbamic chloride and Example 183D, respectively, in Example200. MS (ESI(−)) m/e 304 (M−H)⁻.

EXAMPLE 398B methyl4-(2-(((2-hydroxyethyl)amino)sulfonyl)-3-methyl-1-benzothien-5-yl)benzoate

The desired product was prepared by substituting Example 398A for5-chloro-2-methyl-1,3-benzoxazole in Example 54A. MS (ESI(−)) m/e 404(M−H)⁻.

EXAMPLE 398C methyl4-(2-(((2-((tert-butyl(dimethyl)silyl)oxy)ethyl)amino)sulfonyl)-3-methyl-1-benzothien-5-yl)benzoate

A solution of Example 398B (200 mg, 0.5 mmol), tert-butyldimethylsilylchloride (85 mg, 0.55 mmol) and imidazole (36 mg, 0.6 mmol) in DMF (5mL) at room temperature was stirred for 24 hours, diluted with ether,filtered through a pad of silica gel, and concentrated to provide thedesired product.

EXAMPLE 398D4-(2-(((2-((tert-butyl(dimethyl)silyl)oxy)ethyl)amino)sulfonyl)-3-methyl-1-benzothien-5-yl)benzoicacid

The desired product was prepared by substituting Example 398C forExample 1A in Example 1B. MS (ESI(−)) m/e 504 (M−H)⁻.

EXAMPLE 398EN-(2-hydroxyethyl)-3-methyl-5-(4-((((3-nitro-4-((2-(phenylthio)ethyl)amino)phenyl)sulfonyl)amino)carbonyl)phenyl)-1-benzothiophene-2-sulfonamide

The desired product was prepared by substituting Example 398D andExample 77B for Example 1B and Example 1C, respectively, in Example 1D.The product was treated with TFA (5 mL), stirred for 2 hours,concentrated, dissolved in toluene, and concentrated again to providethe desired product. MS (ESI(−)) m/e 725 (M−H)⁻; ¹H NMR (300 MHz,DMSO-d₆) δ2.70 (s, 3H), 2.95 (dt, 2H), 3.28 (t, 2H), 3.38 (dt, 2H), 3.66(dt, 2H), 4.22 (m, 1H), 4.70 (m, 1H), 7.19 (d, 1H), 7.24-7.37 (m, 4H),7.80 (m, 4H), 7.92 (dd, 1H), 7.96 (d, 2H), 8.61 (d, 1H), 8.78 (t, 1H).

EXAMPLE 399N-(1,1′-biphenyl-4-ylcarbonyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting 4-biphenylcarboxylicacid and Example 77B for Example 1B and Example 1C, respectively, inExample 1D. MS (ESI(−)) m/e 532 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ8.78(t, 1H), 8.62 (d, 1H), 7.97 (d, 2H), 7.94 (dd, 1H), 7.79 (m, 2H), 7.73(d, 2H), 7.49 (t, 2H), 7.42 (t, 1H), 7.38 (m, 2H), 7.27 (m, 2H), 7.18(m, 2H), 3.66 (q, 2H), 3.29 (t, 2H).

EXAMPLE 4003-nitro-N-(4-(5-nitropyridin-2-yl)benzoyl)-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting2-chloro-5-nitropyridine for 2,8-bistrifluoromethyl-3-chloroquinoline inExample 319. MS (ESI) m/e 580 578 (M+H)⁺, (M−H)⁻; ¹H NMR (500 MHz,DMSO-d₆) δ9.47 (d, 1H), 8.78 (t, 1H), 8.69 (dd, 1H), 8.64 (d, 1H), 8.36(d, 1H), 8.31 (d, 2H), 8.05 (d, 2H), 7.95 (dd, 1H), 7.37 (dt, 2H), 7.27(td, 2H), 7.22 (d, 1H), 7.17 (tt, 1H), 3.68 (q, 2H), 3.29 (t, 2H).

EXAMPLE 401N-(4-(2-cyano-3-methyl-1-benzothien-5-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamideEXAMPLE 401A 5-chloro-3-methyl-1-benzothiophene-2-carbonitrile

A mixture of 2-bromo-5-chloro-3-methylbenzo(b)thiophene (1.00 g, 3.82mmol), zinc cyanide (247 mg, 2.10 mmol), and Pd(PPh₃)₄ (440 mg, 0.38mmol) in DMF (15 mL) was heated to 80° C. for 16 hours, added to water(50 mL), and extracted with 30% ethyl acetate/hexanes (3×100 mL). Thecombined extracts were washed with brine (20 mL), dried (Na₂SO₄),filtered, and concentrated. The concentrate was purified by flash columnchromatography on silica gel with 10% ethyl acetate/hexanes to providethe desired product.

EXAMPLE 401B methyl 4-(2-cyano-3-methyl-1-benzothien-5-yl)benzoate

A mixture of Example 401A (557 mg, 2.68 mmol),(4-methoxycarbonylphenyl)-boronic acid (675 mg, 3.75 mmol), Pd(OAc)₂ (36mg, 0.16 mmol), 2-(di-tert-butylphosphino)biphenyl (63 mg, 0.21 mmol),and KF (467 mg, 8.04 mmol) in THF (10 mL) was heated to 60° C. for 16hours and concentrated. The concentrate was purified by flash columnchromatography on silica gel with 10% ethyl acetate/hexanes to providethe desired product.

EXAMPLE 401C 4-(2-cyano-3-methyl-1-benzothien-5-yl)benzoic acid

The desired product was prepared by substituting Example 401B forExample 1A in Example 1B.

EXAMPLE 401DN-(4-(2-cyano-3-methyl-1-benzothien-5-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 401C andExample 77B for Example 1B and Example 1C, respectively, in Example 1D.MS (ESI) m/e 627, 629 (M−H)⁻, (M+H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ2.70(s, 3H), 3.27 (t, 2H), 3.62 (dt, 2H), 7.05 (d, 1H), 7.19 (tt, 1H), 7.29(tt, 2H), 7.38 (dt, 2H), 7.82 (d, 2H), 7.91 (dd, 1H), 7.97 (dd, 1H),8.01 (d, 2H), 8.20 (d, 1H), 8.30 (d, 1H), 8.55 (d, 1H), 8.58 (t, 1H).

EXAMPLE 402N-((4′-fluoro-1,1′-biphenyl-4-yl)carbonyl)-4-((3-methoxy-2-(phenylthio)propyl)amino)-3-nitrobenzenesulfonamideandN-((4′-fluoro-1,1′-biphenyl-4-yl)carbonyl)-4-((2-methoxy-1-((phenylthio)methyl)ethyl)amino)-3-nitrobenzenesulfonamideEXAMPLE 402A 3-methoxy-2-(phenylthio)propan-1-ol and1-methoxy-3-(phenylthio)propan-2-ol

The desired product was prepared by substituting glycidyl methyl etherfor cyclohexene oxide in Example 7A.

EXAMPLE 402B ((2-azido-1-(methoxymethyl)ethyl)thio)benzene compound and((2-azido-3-methoxypropyl)thio)benzene

The desired product was prepared by substituting Example 402A forExample 7A in Example 7B.

EXAMPLE 402C4-((3-methoxy-2-(phenylthio)propyl)amino)-3-nitrobenzenesulfonamidecompound and4-((2-methoxy-1-((phenylthio)methyl)ethyl)amino)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 402B forExample 393B in Example 393C.

EXAMPLE 402DN-((4′-fluoro-1,1′-biphenyl-4-yl)carbonyl)-4-((3-methoxy-2-(phenylthio)propyl)amino)-3-nitrobenzenesulfonamideandN-((4′-fluoro-1,1′-biphenyl-4-yl)carbonyl)-4-((2-methoxy-1-((phenylthio)methyl)ethyl)amino)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 402C forExample 1C in Example 1D. MS (ESI(−)) m/e 594 (M−H)⁻; ¹H NMR (300 MHz,DMSO-d₆), mixture of two isomers, ratio (1.2:1) δ8.86 (br t, 1/2H),8.61, 8.59 (2d, 1H), 8.53 (br d, 1/2H), 7.96 (2d, 2H), 7.89 (2dd, 1H),7.78 (m, 4H), 7.45-7.10 (m, 8H), 4.25 (m, 1/2H), 3.80-3.50 (m, 4.5H),3.29, 3.27 (2s, 3H).

EXAMPLE 403N-(4-(2-hydroxyquinolin-8-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamideEXAMPLE 403A 4-(2-hydroxyquinolin-8-yl)benzoic acid

The desired product was prepared by substituting Example 336B forExample 1A in Example 1B.

EXAMPLE 403BN-(4-(2-hydroxyquinolin-8-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 403A andExample 77B for Example 1B and Example 1C, respectively, in Example 1D.MS (ESI(−)) m/e 599 (M−H)⁻; ¹H NMR (400 MHz, DMSO-d₆) δ8.77 (t, 1H),8.53 (d, 1H), 8.02 (d, 2H), 8.00 (d, 1H), 7.95 (dd, 1H), 7.72 (dd, 1H),7.60 (d, 2H), 7.40 (dd, 1H), 7.37 (m, 2H), 7.38 (t, 2H), 7.22 (d, 1H),7.19 (tt, 1H), 6.53 (d, 1H), 3.67 (q, 2H), 3.28 (t, 2H).

EXAMPLE 404N-((2′-methoxy-4′-(morpholin-4-ylmethyl)-1,1′-biphenyl-4-yl)carbonyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamideEXAMPLE 404A methyl2′-methoxy-4′-(morpholin-4-ylmethyl)-1,1′-biphenyl-4-carboxylate

A mixture of Example 122I (135 mg, 0.50 mmol), morpholine (100 mg), 1Msodium cyanoborohydride in THF (1 mL) in methanol (2 mL) and acetic acid(0.3 mL) was stirred for 18 hours, diluted with ethyl acetate (100 mL),washed sequentially with 2M sodium carbonate (10 mL), water (20 mL), andbrine (10 mL), dried (MgSO₄), filtered, and concentrated. Theconcentrate was purified by flash column chromatography on silica gelwith 30-100% ethyl acetate/hexanes to provide the desired product. MS(DCI(+)) m/e 342 (M+H)⁺.

EXAMPLE 404BN-((2′-methoxy-4′-(morpholin-4-ylmethyl)-1,1′-biphenyl-4-yl)carbonyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 404A andExample 77B for Example 5C and Example 3A, respectively, in Example 5D.MS (ESI(−)) m/e 663 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ8.74 (t, 1H),8.61 (d, 1H), 7.92 (m, 3H), 7.56 (d, 2H), 7.38 (m, 3H), 7.28 (m, 3H),7.21-7.10 (m, 3H), 3.80 (s, 2H), 3.76 (s, 3H), 3.66 (q, 2H), 3.40-3.20(m, 4 H, buried in water peak).

EXAMPLE 405 tert-butyl4-(4-((((3-nitro-4-((2-(phenylthio)ethyl)amino)phenyl)sulfonyl)amino)carbonyl)phenyl)piperazine-1-carboxylate

The desired product was prepared by substituting4-(4-((neopentyloxy)carbonyl)piperazin-1-yl)benzoic acid and Example 77Bfor Example 1B and Example 1C, respecitvely, in Example 1D. MS (ESI(−))m/e 640 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ8.77 (t, 1H), 8.60 (d, 1H),7.91 (dd, 1H), 7.76 (d, 2H), 7.36 (d, 2H), 7.14-7.29 (m, 4H), 6.94 (d,2H), 3.66 (q, 2H), 3.37-3.45 (m, 4H), 3.23-3.30 (m, 6H), 1.41 (s, 9H).

EXAMPLE 406N˜2˜-(4-((((4′-fluoro-1,1′-biphenyl-4-yl)carbonyl)amino)sulfonyl)-2-nitrophenyl)-N˜1˜,N˜1˜-bis(4-(N-(4-((((4′-fluoro-1,1′-biphenyl-4-yl)carbonyl)amino)sulfonyl)-2-nitrophenyl)-S-phenylcysteinyl)morpholin-3-yl)-S-phenylcysteinamide

The desired product was prepared by substituting Example 180B forExample 1C in Example 1D. MS (ESI(−)) m/e 663 (M−H)⁻; ¹H NMR (300 MHz,dmso-d₆) δ8.95 (d, 1H), 8.49 (d, 1H), 7.97 (d, 2H), 7.91 (dd, 1H), 7.72(m, 4H), 7.60 (d, 2H), 7.27 (m, 4H), 7.15 (m, 4H), 5.27 (m, 1H), 3.57(m, 4H), 3.50 (m, 4H), 3.37 (dd, 1H), 3.20 (m, 1H).

EXAMPLE 407N-(4-(4,4-dimethylcyclohexyl)benzoyl)-4-((2-morpholin-4-yl-1-((phenylthio)methyl)ethyl)amino)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 77A and Example245A for Example 5C and Example 3A, respectively, in Example 5D. MS(ESI(−)) m/e 665 (M−H)⁻; ¹H NMR (400 MHz, methanol-d₄) δ8.66 (d, 1H),7.90 (dd, 1H), 7.84 (d, 2H), 7.28 (m, 4H), 7.07 (m, 3H), 6.91 (d, 1H),4.14 (m, 1H), 3.30 (t, 4H), 3.40 (dd, 1H), 3.21 (dd, 1H), 2.72 (m, 2H),2.51 (m, 5H), 1.64 (m, 4H), 1.49 (m, 2H), 1.35 (m, 2H), 0.98 (s, 3H),0.94 (s, 8H).

EXAMPLE 4084-((2-amino-1-((phenylthio)methyl)ethyl)amino)-N-((4′-fluoro-1,1′-biphenyl-4-yl)carbonyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 434D forExample 384E in Example 125. MS (ESI(−)) m/e 579 (M−H)⁻; ¹H NMR (300MHz, dmso-d₆) δ8.59 (d, 1H), 8.33 (d, 1H), 8.05 (m, 3H), 7.97 (d, 2H),7.87 (dd, 1H), 7.78 (m, 4H), 7.35-7.11 (m, 8H), 4.40 (m, 1H), 3.25 (m,2H), (remaining 2 protons are buried under water peak, 3.50-3.30 ppm).

EXAMPLE 409 benzyl4-(4-((((3-nitro-4-((2-(phenylthio)ethyl)amino)phenyl)sulfonyl)amino)carbonyl)phenyl)piperazine-1-carboxylate

The desired product was prepared by substituting benzyloxyacetylchloride for 2-methoxyethyl chloroformate in Example 325. MS (ESI(−))m/e 674 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ8.74 (t, 1H), 8.58 (d, 1H),7.90 (dd, 1H), 7.76 (d, 2H), 7.39-7.14 (m, 11H), 6.93 (d, 2H), 5.10 (s,2H), 3.65 (q, 2H), 3.51-3.57 (m, 4H), 3.32-3.23 (m, 6H).

EXAMPLE 4103-nitro-4-((2-(phenylthio)ethyl)amino)-N-(4-(1-(pyridin-2-ylcarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)benzoyl)benzenesulfonamide

The desired product was prepared by substituting picolinoyl chloride for4-morpholinecarbonyl chloride in Example 317. MS (ESI(−)) m/e 642(M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ8.80 (br t, 1H), 8.62 (d, 1H), 7.95(m, 2H), 7.85 (d, 2H), 7.62-7.48 (m, 4H), 7.40-7.15 (m, 76H), 6.45 and6.25 (2m, 1H), 4.32 and 4.12 (2d, 2H), 3.92 (t, 2H), 3.65 (m, 2H), 3.25(t,2H), 2.62 (m, 2H).

EXAMPLE 411N,N-diethyl-3-methyl-5-(4-((((3-nitro-4-((2-(phenylthio)ethyl)amino)phenyl)sulfonyl)amino)carbonyl)phenyl)-1-benzothiophene-2-sulfonamideEXAMPLE 411A5-chloro-N,N-diethyl-3-methyl-1-benzothiophene-2-sulfonamide

The desired product was prepared by substituting2-chlorosulfonyl-5-chloro-3-methylbenzthiophene and dimethylamine fordimethylcarbamic chloride and Example 183D, respectively, in Example200. MS (ESI(+)) m/e 318 (M+H)⁺.

EXAMPLE 411B methyl4-(2-((diethylamino)sulfonyl)-3-methyl-1-benzothien-5-yl)benzoate

The desired product was prepared by substituting Example 411A for5-chloro-2-methyl-1,3-benzoxazole in Example 54A.

EXAMPLE 411C4-(2-((diethylamino)sulfonyl)-3-methyl-1-benzothien-5-yl)benzoic acid

The desired product was prepared by substituting Example 411B forExample 1A in Example 1B. MS (ESI(−)) m/e 402 (M−H)⁻.

EXAMPLE 411DN,N-diethyl-3-methyl-5-(4-((((3-nitro-4-((2-(phenylthio)ethyl)amino)phenyl)sulfonyl)amino)carbonyl)phenyl)-1-benzothiophene-2-sulfonamide

The desired product was prepared by substituting Example 411C andExample 77B for Example 1B and Example 1C, respectively, in Example 1D.MS (ESI(−)) m/e 737 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ1.10 (t, 6H),2.72 (s, 3H), 3.28 (q, 4H), 3.36 (t, 2H), 3.62 (dt, 2H), 7.00 (d, 1H),7.20 (t, 1H), 7.31 (t, 2H), 7.41 (d, 2H), 7.77 (d, 2H), 7.90 (d, 2H),8.01 (d, 2H), 8.12 (d, 1H), 8.22 (s, 1H), 8.51 (t, 1H), 8.53 (t, 1H).

EXAMPLE 412N-(4-(3-methyl-2-morpholin-4-yl-1-benzothien-5-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamideEXAMPLE 412A 4-(5-chloro-3-methyl-1-benzothien-2-yl)morpholine

A mixture of 2-bromo-5-chloro-3-methylbenzthiophene (523 mg, 2 mmol),morpholine (210 uL, 2.4 mmol), Pd₂dba₃ (37 mg, 0.04 mmol), BINAP (62 mg,0.1 mmol), and sodium tert-butoxide (270 mg, 2.8 mmol) in toluene (5 mL)was stirred at 80° C. for 18 hours. The reaction mixture was purified byflash column chromatography on silica gel with 20% ethyl acetate/hexanesto provide the desired product. MS (ESI(+)) m/e 268 (M+H)⁺.

EXAMPLE 412B methyl4-(3-methyl-2-morpholin-4-yl-1-benzothien-5-yl)benzoate

The desired product was prepared by substituting Example 412A for5-chloro-2-methyl-1,3-benzoxazole in Example 54A.

EXAMPLE 412C 4-(3-methyl-2-morpholin-4-yl-1-benzothien-5-yl)benzoic acid

The desired product was prepared by substituting Example 412B forExample 1A in Example 1B. MS (ESI(−)) m/e 352 (M−H)⁻.

EXAMPLE 412DN-(4-(3-methyl-2-morpholin-4-yl-1-benzothien-5-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was preparede by substituting Example 412C andExample 77B for Example 1B and Example 1C, respectively, in Example 1D.MS (ESI(−)) m/e 687 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ2.31 (s, 3H),2.95 (m, 4H), 3.28 (t, 2H), 3.67 (dt, 2H), 3.79 (m, 4H), 7.19 (m, 2H),7.28 (t, 2H), 7.38 (d, 2H), 7.48 (t, 1H), 7.62 (d, 1H), 7.85-8.00 (m,6H), 8.62 (d, 1H), 8.78 (t, 1H).

EXAMPLE 413N-(4-(2-methyl-1,3-benzothiazol-5-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 17A and Example77B for Example 1B and Example 1C, respectively, in Example 1D. MS (ESI)m/e 603, 605 (M−H)⁻, (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ2.83 (s, 3H),3.28 (t, 2H), 3.62 (dt, 2H), 7.02 (d, 1H), 7.19 (tt, 1H), 7.30 (td, 2H),7.39 (dt, 2H), 7.73 (dd, 1H), 7.74 (d, 2H), 7.89 (dd, 1H), 7.98 (d, 2H),8.10 (d, 1H), 8.19 (d, 1H), 8.53 (d, 1H), 8.55 (t, 1H).

EXAMPLE 414N-(4-(3-methyl-1-pentyl-1H-pyrazol-4-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamideandN-(4-(5-methyl-1-pentyl-1H-pyrazol-4-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamideEXAMPLE 414A 4-bromo-5-methyl-1-pentyl-1H-pyrazole and4-bromo-3-methyl-1-pentyl-1H-pyrazole

The desired product was prepared by substituting 1-iodopentane and4-bromo-3-methylpyrazole for 1-bromooctane and 4-iodopyrazole,respectively, in Example 198A. MS (ESI(+)) m/e 231, 233 (M+H)⁺.

EXAMPLE 414B 4-(5-methyl-1-pentyl-1H-pyrazol-4-yl)benzoic acid and4-(3-methyl-1-pentyl-1H-pyrazol-4-yl)benzoic acid

The desired product was prepared by substituting Example 414A for6-bromoindole in Example 4A. MS (ESI) m/e 271 (M−H)⁻.

EXAMPLE 414CN-(4-(3-methyl-1-pentyl-1H-pyrazol-4-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamideandN-(4-(5-methyl-1-pentyl-1H-pyrazol-4-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 414B andExample 77B for Example 1B and Example 1C, respectively, in Example 1D.MS (ESI(−)) m/e 606 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ0.86 (t, 3H),1.29 (m, 4H), 1.78 (m, 2H), 2.30 (s, 1.8H), 2.38 (s, 1.2H), 3.27 (t,2H), 3.61 (dt, 2H), 4.01 (t, 2H), 7.01 (d, 1H), 7.20 (t, 1H), 7.31 (t,2H), 7.40 (m, 4H), 7.90 (m, 3H), 7.99 (s, 1H), 8.51 (d, 1H), 8.54 (t,1H).

EXAMPLE 4154-((2-adamantylmethyl)amino)-N-(4-(5-fluoroquinolin-8-yl)benzoyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 255A forExample 108A in Example 389B. MS (ESI(−)) m/e 613 (M−H)⁻; ¹H NMR (400MHz, DMSO-d₆) δ8.99 (dd, 1H), 8.55 (m, 2H), 8.40 (t, 1H), 7.97 (d, 2H),7.92 (dd, 1H), 7.78 (dd, 1H), 7.72 (d, 1H), 7.67 (dd, 1H), 7.60 (d, 2H),7.54 (dd, 1H), 7.18 (d, 1H), 3.14 (d, 2H), 1.98 (m, 3H), 1.72-1.55 (m,12H).

EXAMPLE 416 methyl2-((4-((((4′-fluoro-1,1′-biphenyl-4-yl)carbonyl)amino)sulfonyl)-2-nitrophenyl)amino)-3-(phenylthio)propylcarbamate

The desired product was prepared by substituting methyl chloroformatefor acetyl chloride in Example 310. MS (ESI(−)) m/e 637 (M−H)⁻; ¹H NMR(300 MHz, DMSO-d₆) δ8.55 (d, 1H), 8.30 (d, 1H), 7.96 (d, 2H), 7.84 (dd,1H), 7.75 (m, 4H), 7.45 (m, 1H), 7.35-7.10 (m, 8H), 4.06 (m, 1H), 4.02(m, 2H), 2.49 (s, 3H), remaining two protons buried under solvent peaks.

EXAMPLE 417N-((2′-methoxy-4′-(methoxymethyl)-1,1′-biphenyl-4-yl)carbonyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamideEXAMPLE 417A methyl4′-(hydroxymethyl)-2′-methoxy-1,1′-biphenyl-4-carboxylate

A solution of Example 122I (270 mg, 0.5 mmol), and sodium borohydride(80 mg) in methanol (5 mL) at room temperature was stirred for 30minutes, diluted with ethyl acetate (70 mL), washed with water (20 mL)and brine (10 mL), dried (MgSO₄), filtered, and concentrated to providethe desired product.

EXAMPLE 417B methyl2′-methoxy-4′-(methoxymethyl)-1,1′-biphenyl-4-carboxylate

A solution of Example 417A (142 mg, 0.5 mmol) in THF (3 mL) at roomtemperature was treated with 60% sodium hydride in oil (40 mg, 1.0 mmol)and methyl iodide (0.30 mmol), stirred for 30 minutes, adjusted to pH<7with 4M HCl in dioxane (0.5 mL), filtered, and concentrated. Theconcentrate was purified by flash column chromatography on silica gelwith 10% ethyl acetate/hexanes to provide the desired product.

EXAMPLE 417CN-((2′-methoxy-4′-(methoxymethyl)-1,1′-biphenyl-4-yl)carbonyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 417B andExample 77B for Example 5C and Example 3A, respectively, in Example 5D.MS (ESI(−)) m/e 606 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ8.72 (t, 1H),8.60 (d, 1H), 7.92 (dd, 1H), 7.89 (d, 2H), 7.54 (d, 2H), 7.37 (m, 2H),7.28 (m, 3H), 7.18 (tt, 1H), 7.06 (s, 1H), 6.97 (d, 1H), 4.45 (s, 2H),3.76 (s, 3H), 3.66 (q, 2H), 3.33 (s, 3H), 3.20 (t, 2H).

EXAMPLE 418 tert-butyl7-(4-(4-((((3-nitro-4-((2-(phenylthio)ethyl)amino)phenyl)sulfonyl)amino)carbonyl)phenyl)-3,6-dihydropyridin-1(2H)-yl)-7-oxoheptylcarbamate

The desired product was prepared by substituting BOC-7-aminoheptanoicacid for BOC-leucine in Example 378. MS (ESI(−)) m/e 764 (M−H)⁻; ¹H NMR(300 MHz, DMSO-d₆) δ8.72 (br t, 1H), 8.60 (d, 1H), 7.92 (dd, 1H), 7.85(d, 2H), 7.55 (d, 2H), 7.40-7.15 (m, 6H), 6.75 (br t, 1H), 6.45 and 6.42(2m, 1H), 4.18 and 4.12 (2d, 2H), 3.65 (m, 4H), 3.40-3.25 (m, 4H), 2.90(m, 2H), 2.45 (m, 2H), 2.45 (m, 2H), 1.50 (m, 2H), 1.35 (s, 9H), 1.25(m, 4H).

EXAMPLE 419N-(4-(2-methyl-1-benzothien-5-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamideEXAMPLE 419A methyl 4-(2-methyl-1-benzothien-5-yl)benzoate

The desired product was prepared by substituting5-chloro-2-methylbenzothiophene for 5-chloro-2-methyl-1,3-benzoxazole inExample 54A.

EXAMPLE 419B 4-(2-methyl-1-benzothien-5-yl)benzoic acid

The desired product was prepared by substituting Example 419A forExample 1A in Example 1B. MS (ESI(−)) m/e 564 (M−H)⁻.

EXAMPLE 419CN-(4-(2-methyl-1-benzothien-5-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 419B andExample 77B for Example 1B and Example 1C, respectively, in Example 1D.MS (ESI(−)) m/e 602 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ2.59 (s, 3H),3.28 (t, 2H), 3.61 (dt, 2H), 7.00 (d, 1H), 7.19 (s, 1H), 7.20 (d, 1H),7.30 (t, 2H), 7.40 (d, 2H), 7.50 (dd, 1H), 7.68 (d, 2H), 7.90 (t, 2H),7.96 (d, 2H), 8.02 (s, 1H), 8.51 (t, 1H), 8.52 (d, 1H).

EXAMPLE 420N-(3-(4-hydroxy-4-methylcyclohex-1-en-1-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamideEXAMPLE 420A 1,4-dioxaspiro(4.5)dec-7-en-8-yl trifluoroacetate

The desired product was prepared by substituting1,4-dioxaspiro(4.5)decan-8-one for 4-tert-butylcyclohexanone in Example5A.

EXAMPLE 420B methyl 4-(1,4-dioxaspiro(4.5)dec-7-en-8-yl)benzoate

The desired product was prepared by substituting Example 420A forExample 5A in Example 5B.

EXAMPLE 420C methyl 4-(4-oxocyclohex-1-en-1-yl)benzoate

A solution of Example 420B (2.2 g) and p-toluenesulfonic acid (100 mg)in acetone (10 mL) was heated to reflux for 10 hours, filtered through apad of silica gel (20 g), and concentrated to provide the desiredproduct.

EXAMPLE 420D methyl 4-(4-hydroxy-4-methylcyclohex-1-en-1-yl)benzoate

A suspension of anhydrous cerium(III) chloride (2.71 g, 11 mmol) in THF(10 mL) at −78° C. was slowly treated with 1.5M methyllithium complexedwith lithium chloride in diethyl ether (6.7 mL), warmed to roomtemperature over 2 hours, and added to a solution of Example 420C (1.15g, 5.0 mmol) in THF (10 mL) at −78° C. The reaction was gradually warmedto room temperature over 4 hours, diluted with ethyl acetate (100 mL),washed with water (45 mL) and brine (10 mL), dried (MgSO₄), filtered,and concentrated. The concentrate was purified by flash columnchromatography on silica gel with 10-30% ethyl acetate/hexanes toprovide the desired product.

EXAMPLE 420E 4-(4-hydroxy-4-methylcyclohex-1-en-1-yl)benzoic acid

The desired product was prepared by substituting Example 420D forExample 1A in Example 1B.

EXAMPLE 420FN-(3-(4-hydroxy-4-methylcyclohex-1-en-1-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 420E andExample 77B for Example 1B and Example 1C, respectively, in Example 1D.MS (ESI(−)) m/e 566 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ8.78 (br t, 1H),8.60 (d, 1H), 7.92 (dd, 1H), 7.85 (d, 2H), 7.50 (d, 2H), 7.40-7.15 (m,6H), 6.20 (m, 1H), 3.70 (m, 2H), 2.40-0.90(m, 8H), 1.25 (s, 3H).

EXAMPLE 421N-((4′-fluoro-1,1′-biphenyl-4-yl)carbonyl)-4-((3-(2-furylmethoxy)-2-(phenylthio)propyl)amino)-3-nitrobenzenesulfonamideandN-((4′-fluoro-1,1′-biphenyl-4-yl)carbonyl)-4-((2-(2-furylmethoxy)-1-((phenylthio)methyl)ethyl)amino)-3-nitrobenzenesulfonamideEXAMPLE 421A 3-(2-furylmethoxy)-2-(phenylthio)propan-1-ol and1-(2-furylmethoxy)-3-(phenylthio)propan-2-ol

The desired products were prepared by substituting furfuryl glycidylether for cyclohexene oxide in Example 7A.

EXAMPLE 421B 2-((3-azido-2-(phenylthio)propoxy)methyl)furan and2-((2-azido-3-(phenylthio)propoxy)methyl)furan

The desired product was prepared by substituting Example 421A forExample 7A in Example 7B.

EXAMPLE 421CN-((4′-fluoro-1,1′-biphenyl-4-yl)carbonyl)-4-((3-(2-furylmethoxy)-2-(phenylthio)propyl)amino)-3-nitrobenzenesulfonamideandN-((4′-fluoro-1,1′-biphenyl-4-yl)carbonyl)-4-((2-(2-furylmethoxy)-1-((phenylthio)methyl)ethyl)amino)-3-nitrobenzenesulfonamide

The desired compound was prepared by substituting Example 421B forExample 393B in Example 393C. MS (ESI(−)) m/e 660 (M−H)⁻; ¹H NMR (300MHz, DMSO-d₆), mixture of two isomers, ratio (2:1) δ8.81 (br t, 2/3H),8.61, 8.59 (2d, 1H), 8.51 (br d, 1/2H), 7.96 (2d, 2H), 7.92, 7.88 (2dd,1H), 7.78 (m, 4H), 7.60, 7.58 (2m, 1H), 7.40-7.10 (m, 8H), 6.49 (m, 2H),4.45 (s, 2H), 4.25 (m, 2/3H), 3.80-3.50 (m, 5H).

EXAMPLE 422 isobutyl4-(4-((((3-nitro-4-((2-(phenylthio)ethyl)amino)phenyl)sulfonyl)amino)carbonyl)phenyl)piperazine-1-carboxylate

The desired product was prepared by substituting isopropyl chloroformatefor 2-methoxyethyl chloroformate in Example 325. MS (ESI(−)) m/e 640(M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ8.75 (t, 1H), 8.59 (d, 1H), 7.91 (dd,1H), 7.76 (d, 2H), 7.39-7.35 (m, 2H), 7.29-7.23 (m, 2H), 7.20-7.14 (m,2H), 6.93 (d, 2H), 3.81 (d, 2H), 3.66 (q, 2H), 3.50-3.44 (m, 4H),3.32-3.23 (m, 6H), 1.94-1.82 (m, 1H), 0.90 (d, 6H).

EXAMPLE 423N-(4-(5-methylpyridin-2-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting2-chloro-5-methylpyridine for 2,8-bistrifluoromethyl-3-chloroquinolinein Example 319. MS (ESI) m/e 549 (M+H)⁺, 547 (M−H)⁻; ¹H NMR (500 MHz,DMSO-d₆) δ7.78 (t, 1H), 8.63 (d, 1H), 8.53 (d, 1H), 8.17 (d, 2H),7.98-7.93 (m, 4H), 7.74 (dd, 1H), 7.37 (dt, 2H), 7.27 (td, 2H), 7.21 (d,1H), 7.17 (tt, 1H), 3.67 (q, 2H), 3.27 (t, 2H), 2.35 (s, 3H).

EXAMPLE 4243-nitro-4-((2-(phenylthio)ethyl)amino)-N-(4-(1H-pyrrol-1-yl)benzoyl)benzenesulfonamide

The desired product was prepared by substituting 4-(N-pyrrolyl)benzoicacid and Example 77B for Example 1B and Example 1C, respectively, inExample 1D. MS (ESI(−)) m/e 521 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ3.26(t, 2H), 3.60 (dt, 2H), 6.27 (s, 2H), 7.00 (d, 1H), 7.20 (t, 1H), 7.31(t, 2H), 7.40 (d, 2H), 7.42 (s, 2H), 7.52 (d, 2H), 7.89 (d, 1H), 7.93(d, 2H), 8.51 (d, 1H), 8.52 (t, 1H).

EXAMPLE 425N-(4-(3-methyl-1-benzothien-5-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamideEXAMPLE 425A methyl 4-(3-methyl-1-benzothien-5-yl)benzoate

The desired product was prepared by substituting5-chloro-3-methylbenzothiophene for 5-chloro-2-methyl-1,3-benzoxazole inExample 54A.

EXAMPLE 425B 4-(3-methyl-1-benzothien-5-yl)benzoic acid

The desired product was prepared by substituting Example 425A forExample 1A in Example 1B. MS (ESI(−)) m/e 267 (M−H)⁻.

EXAMPLE 425CN-(4-(3-methyl-1-benzothien-5-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 425B andExample 77B for Example 1B and Example 1C, respectively, in Example 1D.MS (ESI(−)) m/e 602 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ2.46 (s, 3H),3.27 (t, 2H), 3.61 (dt, 2H), 7.00 (d, 1H), 7.20 (t, 1H), 7.31 (t, 2H),7.41 (m, 3H), 7.70 (dd, 1H), 7.72 (d, 2H), 7.90 (dd, 1H), 7.99 (d, 2H),8.02 (d, 2H), 8.51 (t, 1H), 8.52 (d, 1H).

EXAMPLE 426N-((4′-fluoro-1,1′-biphenyl-4-yl)carbonyl)-4-(((1S)-3-hydroxy-1-((phenylthio)methyl)propyl)amino)-3-nitrobenzenesulfonamideEXAMPLE 426A(3S)-3-((4-(aminosulfonyl)-2-nitrophenyl)amino)-4-(phenylthio)butanoicacid

The desired product was prepared by substituting Fmoc-L-Asp(OtBu)-OH forFmoc-D-Asp(OtBu)-OH in Examples 122A-122E.

EXAMPLE 426BN-((4′-fluoro-1,1′-biphenyl-4-yl)carbonyl)-4-(((1S)-3-hydroxy-1-((phenylthio)methyl)propyl)amino)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 426A forExample 122E in Example 280.

EXAMPLE 427N-((4′-(3-(dimethylamino)propyl)-2′-methoxy-1,1′-biphenyl-4-yl)carbonyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamideEXAMPLE 427A methyl4′-(3-(dimethylamino)-3-oxopropyl)-2′-methoxy-1,1′-biphenyl-4-carboxylate

The desired product was prepared by substituting dimethylamine formorpholine in Example 122M.

EXAMPLE 427B methyl4′-(3-(dimethylamino)propyl)-2′-methoxy-1′-biphenyl-4-carboxylate

The desired product was prepared by substituting Example 427A forExample 122F in Example 122G.

EXAMPLE 427CN-((4′-(3-(dimethylamino)propyl)-2′-methoxy-1,1′-biphenyl-4-yl)carbonyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 427B andExample 77B for Example 5C and Example 3A, respectively, in Example 5D.MS (ESI(−)) m/e 647 (M−H)⁻; ¹H NMR (500 MHz, methanol-d₄) δ8.80 (d, 1H),8.02 (dd, 1H), 7.83 (d, 2H), 7.59 (d, 2H), 7.36 (m, 2H), 7.26 (d, 1H),7.21 (tt, 2H), 7.16 (tt, 1H), 7.06 (d, 1H), 6.98 (d, 1H), 6.92 (dd, 1H),4.06 (t, 2H), 3.80 (s, 3H), 3.69 (t, 2H), 3.28 (t, 2H), 3.15 (m, 2H),2.08 (m, 2H), 2.01 (s, 3H), 1.99 (s, 3H).

EXAMPLE 4284-((3-(dimethylamino)-1-((phenylthio)methyl)propyl)amino)-N-((4′-fluoro-1,1′-biphenyl-4-yl)carbonyl)-3-nitrobenzenesulfonamideEXAMPLE 428A4-((3-(dimethylamino)-1-((phenylthio)methyl)propyl)amino)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Fmoc-DL-Asp(OtBu)-OHfor Fmoc-D-Asp(OtBu)-OH in Examples 122A-122G.

EXAMPLE 428B4-((3-(dimethylamino)-1-((phenylthio)methyl)propyl)amino)-N-((4′-fluoro-1,1′-biphenyl-4-yl)carbonyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 428A forExample 3A in Example 5D. MS (ESI(−)) m/e 621 (M−H)⁻; ¹H NMR (500 MHz,methanol-d₄) δ8.72 (d, 1H), 7.98 (m, 3H), 7.68 (m, 4H), 7.26 (m, 2H),7.18 (tt, 2H), 7.11 (m, 3H), 7.02 (d, 1H), 4.17 (m, 1H), 3.40 (d, 1H),3.25 (m, 3H), 2.88 (s, 6H), 2.30 (m, 1H), 2.20 (m, 1H).

EXAMPLE 429 tert-butyl3-(2-methoxy-4′-((((3-nitro-4-((2-(phenylthio)ethyl)amino)phenyl)sulfonyl)amino)carbonyl)-1,1′-biphenyl-4-yl)propanoate

The desired product was prepared by substituting Example 122K andExample 77B for Example 5C and Example 3A, respectively, in Example 5D.MS (ESI(−)) m/e 690 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ8.79 (t, 1H),8.62 (d, 1H), 7.94 (dd, 1H), 7.88 (d, 2H), 7.57 (d, 2H), 7.37 (m, 2H),7.30-7.14 (m, 5H), 7.02 (d, 1H), 6.92 (dd, 1H), 3.76 (s, 3H), 3.67 (q,2H), 3.28 (d, 2H), 2.85 (t, 2H), 2.57 (t, 2H), 1.39 (s, 9H).

EXAMPLE 430N-(4-(1-(cyclohexylmethyl)-2-methyl-1H-benzimidazol-5-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamideEXAMPLE 430A 4-bromo-N¹-(cyclohexylmethyl)benzene-1,2-diamine

The desired product was prepared by substituting cyclohexylmethylaminefor butylamine in Examples 166A and 166B.

EXAMPLE 430B 5-bromo-1-(cyclohexylmethyl)-2-methyl-1H-benzimidazole

The desired product was prepared by substituting Example 430A and aceticacid for Example 343A and valeric acid, respectively, in Example 343B.

EXAMPLE 430C4-(1-(cyclohexylmethyl)-2-methyl-1H-benzimidazol-5-yl)benzoic acid

The desired product was prepared by substituting Example 430B for6-bromoindole in Example 4A.

EXAMPLE 430DN-(4-(1-(cyclohexylmethyl)-2-methyl-1H-benzimidazol-5-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 430C andExample 77B for Example 1B and Example 1C, respectively, in Example 1D.MS (ESI) m/e 682, 684 (M−H)⁻, (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆)δ1.03-1.25 (m, 4H), 1.44-1.98 (m, 7H), 2.54 (s, 3H), 3.27 (t, 2H), 3.61(dt, 2H), 4.04 (d, 2H), 6.99 (d, 1H), 7.20 (tt, 1H), 7.31 (td, 2H), 7.40(dd, 2H), 7.50 (dd, 1H), 7.56 (d, 1H), 7.64 (d, 2H), 7.78 (s, 1H), 7.89(dd, 1H), 7.95 (d, 2H), 8.53 (d, 1H), 8.53 (t, 1H).

EXAMPLE 431N-((2′-methoxy-4′-(3-methoxypropyl)-1,1′-biphenyl-4-yl)carbonyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamideEXAMPLE 431A methyl4′-(3-hydroxypropyl)-2′-methoxy-1,1′-biphenyl-4-carboxylate

The desired product was prepared by substituting Example 122L forExample 122E in Example 280A.

EXAMPLE 431B methyl2′-methoxy-4′-(3-methoxypropyl)-1,1′-biphenyl-4-carboxylate

The desired product was prepared by substituting Example 431A forExample 417A in Example 417B.

EXAMPLE 431CN-((2′-methoxy-4′-(3-methoxypropyl)-1,1′-biphenyl-4-yl)carbonyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 431B andExample 77B for Example 5C and Example 3A, respectively, in Example 5D.MS (ESI(−)) m/e 634 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ8.65 (t, 1H),8.57 (d, 1H), 7.90 (dd, 1H), 7.88 (d, 2H), 7.47 (d, 2H), 7.39 (m, 2H),7.30 (tt, 2H), 7.20 (m, 2H), 7.09 (d, 1H), 6.95 (d, 1H), 6.86 (dd, 1H),3.76 (s, 3H), 3.64 (q, 2H), 3.45 (t, 2H), 3.26 (t, 2H), 3.25 (s, 3H),2.64 (t, 2H), 1.85 (m, 2H).

EXAMPLE 432N-((4′-(4-(2,5-dimethoxyphenyl)-1,3-oxazol-2-yl)-1,1′-biphenyl-4-yl)carbonyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamideEXAMPLE 432A 2-(4-bromophenyl)-4-(2,5-dimethoxyphenyl)-1,3-oxazole

The desired product was prepared by substituting2-bromo-2′,5′-dimethoxyacetophenone for 2-bromo-4′-methylacetophenone inExample 186B. MS (DCI) m/e 360, 362 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆)δ8.52 (s, 1H), 8.02-7.99 (m, 2H), 7.80-7.77 (m, 2H), 7.66 (d, 1H), 7.07(d, 1H), 6.93 (dd, 1H), 3.91 (s, 3H), 3.79 (s, 3H).

EXAMPLE 432B ethyl4′-(4-(2,5-dimethoxyphenyl)-1,3-oxazol-2-yl)-1,1′-biphenyl-4-carboxylate

The desired product was prepared by substituting Example 432A forExample 186B in Example 186C. MS (DCI) m/e 430 (M+H)⁺; ¹H NMR (300 MHz,DMSO-d₆) δ8.54 (s, 1H), 8.21-8.18 (m, 2H), 8.10-8.07 (m, 2H), 7.98-7.95(m, 2H), 7.94-7.92 (m, 2H), 7.70 (d, 1H), 7.09 (d, 1H), 6.94 (dd, 1H),4.36 (q, 2H), 3.92 (s, 3H), 3.81 (s, 3H), 1.36 (t, 3H).

EXAMPLE 432C4′-(4-(2,5-dimethoxyphenyl)-1,3-oxazol-2-yl)-1,1′-biphenyl-4-carboxylicacid

The desired product was prepared by substituting Example 432B forExample 186C in Example 186D. MS (DCI) m/e 402 (M+H)⁺; ¹H NMR (300 MHz,DMSO-d₆) δ8.53 (s, 1H), 8.19-8.18 (m, 2H), 8.07-8.06 (m, 2H), 7.96-7.95(m, 2H), 7.91-7.89 (m, 2H), 7.70 (d, 1H), 7.09 (d, 1H), 6.94 (dd, 1H),3.92 (s, 3H), 3.81 (s, 3H).

EXAMPLE 432DN-((4′-(4-(2,5-dimethoxyphenyl)-1,3-oxazol-2-yl)-1,1′-biphenyl-4-yl)carbonyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 432C andExample 77B for Example 1B and Example 1C, respectively, in Example 1D.MS (DCI) m/e 737 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ12.55 (br s, 1H),8.81, (t, 1H), 8.65 (d, 1H), 8.54 (s, 1H), 8.19-8.16 (m, 2H), 8.03-8.00(m, 2H), 7.97-7.89 (m, 5H), 7.68 (d, 1H), 7.39-7.36 (m, 2H), 7.30-7.18(m, 4H), 7.08 (d, 1H), 6.93 (dd, 1H), 3.92 (s, 3H), 3.80 (s, 3H), 3.68(q, 2H), 3.30 (q, 2H).

EXAMPLE 433N-(4-(1-(cyclohexylmethyl)-1H-benzimidazol-5-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamideEXAMPLE 433A 4-bromo-N¹-(cyclohexylmethyl)benzene-1,2-diamine

The desired product was prepared by substituting cyclohexylmethylaminefor butylamine in Examples 166A and 166B.

EXAMPLE 433B 5-bromo-1-(cyclohexylmethyl)-1H-benzimidazole

The desired product was prepared by substituting Example 433A forExample 170A in Example 170B.

EXAMPLE 433CN-(4-(1-(cyclohexylmethyl)-1H-benzimidazol-5-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 433B andExample 214E for 6-bromoindole and 4-(dihydroxyboryl)benzoic acid,respectively, in Example 4A. MS (ESI) m/e 668, 670 (M−H)⁻, (M+H)⁺; ¹HNMR (300 MHz, DMSO-d₆) δ0.95-1.25 (m, 5H), 1.47-1.73 (m, 5H), 1.85 (m,1H), 3.28 (t, 2H), 3.62 (dt, 2H), 4.12 (d, 2H), 6.99 (d, 1H), 7.19 (tt1H), 7.30 (t, 2H), 7.39 (d, 2H), 7.45-7.62 (m, 2H), 7.66 (t, 2H),7.85-7.94 (m, 4H), 8.22 (s, 1H), 8.52 (d, 1H), 8.54 (t, 1H).

EXAMPLE 4344-((2-azido-1-((phenylthio)methyl)ethyl)amino)-N-((4′-fluoro-1,1′-biphenyl-4-yl)carbonyl)-3-nitrobenzenesulfonamideEXAMPLE 434A methylN-(4-(aminosulfonyl)-2-nitrophenyl)-S-phenylcysteinate

The desired product was prepared by substituting Example 175A andExample 122C for Example 175B and Example 175C, respectively, in Example175D.

EXAMPLE 434B4-((2-hydroxy-1-((phenylthio)methyl)ethyl)amino)-3-nitrobenzenesulfonamide

A solution of Example 434A (1.42 g, 3.45 mmol) in THF (10 mL) andmethanol (1 mL) at room temperature was slowly treated with lithiumborohydride (100 mg), stirred for 3 hours, as diluted with ethyl acetate(100 mL), washed with water (45 mL) and brine (10 mL), dried (MgSO₄),filtered, and concentrated to provide the desired product. MS (ESI(+))m/e 384 (M+H).

EXAMPLE 434C4-((2-azido-1-((phenylthio)methyl)ethyl)amino)-3-nitrobenzenesulfonamide

A solution of Example 434B (1.01 g, 2.6 mmol) andN,N-diisopropylethylamine (0.70 mL, 4.0 mmol) in dichloromethane (5 mL)and DMF (5 mL) at room temperature was treated with methanesulfonylchloride (0.22 mL, 2.90 mmol), stirred for 1 hour, and concentrated toremove the dichloromethane. The resulting DMF solution was treated withsodium azide (1.95 g, 30 mmol) and tetrabutylammonium iodide (100 mg),heated to 50° C. for 16 hours, diluted with ethyl acetate (200 mL),washed with water (100 mL) and brine (50 mL), dried (MgSO₄), filtered,and concentrated to provide the desired product.

EXAMPLE 434D4-((2-azido-1-((phenylthio)methyl)ethyl)amino)-N-((4′-fluoro-1,1′-biphenyl-4-yl)carbonyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 434C forExample 1C in Example 1D. MS (ESI(−)) m/e 605 (M−H)⁻; ¹H NMR (300 MHz,DMSO-d₆) δ8.59 (d, 1H), 8.42 (d, 1H), 7.97 (d, 2H), 7.92 (dd, 1H), 7.78(m, 4H), 7.35-7.1 (m, 7H), 4.34 (m, 1H), 3.82 (dd, 1H), 3.69 (dd, 1H),3.37 (m, 2H).

EXAMPLE 435 tert-butyl(3R)-3-((4-((((4′-fluoro-1,1′-biphenyl-4-yl)carbonyl)amino)sulfonyl)-2-nitrophenyl)amino)-4-(phenylthio)butanoate

The desired product was prepared by substituting Example 122D forExample 1C in Example 1D. MS (ESI(−)) m/e 664 (M−H)⁻; ¹H NMR (300 MHz,methanol-d₄) δ8.73 (d, 1H), 8.58 (d, 1H), 7.95 (dd, 1H), 7.93 (d, 2H),7.70 (m, 4H), 7.28 (m, 2H), 7.23-7.12 (m, 5H), 6.98 (d, 1H), 4.40 (m,1H), 2.78 (m, 2H), 1.36 (s, 9H), remaining two protons are buried undersolvent peaks (3.35-3.28 ppm).

EXAMPLE 4368-(4-((((3-nitro-4-((2-(phenylthio)ethyl)amino)phenyl)sulfonyl)amino)carbonyl)phenyl)quinoline-2-carboxylicacid EXAMPLE 436A methyl 8-((trifluoroacetyl)oxy)quinoline-2-carboxylate

The desired product was prepared by substituting methyl8-hydroxyquinoline-2-carboxylate for vanillin in Example 122H.

EXAMPLE 436B8-(4-((((3-nitro-4-((2-(phenylthio)ethyl)amino)phenyl)sulfonyl)amino)carbonyl)phenyl)quinoline-2-carboxylicacid

The desired product was prepared by substituting Example 436A forExample 389A in Example 389B. MS (ESI(−)) m/e 627 (M−H)⁻; ¹H NMR (400MHz, DMSO-d₆) δ8.8.77 (t, 1H), 8.66 (d, 1H), 8.52 (d, 1H), 8.14 (d, 2H),7.97 (d, 2H), 7.96 (dd, 1H), 7.93 (dd, 1H), 7.87 (d, 2H), 7.82 (dd, 1H),7.38 (m, 2H), 7.28 (tt, 2H), 7.22 (d, 1H), 7.19 (tt, 1H), 3.67 9q, 2H),3.28 (t, 2H).

EXAMPLE 4373-(2-methoxy-4′-((((3-nitro-4-((2-(phenylthio)ethyl)amino)phenyl)sulfonyl)amino)carbonyl)-1,1′-biphenyl-4-yl)-N,N-dimethylpropanamide

The desired product was prepared by substituting Example 427A andExample 77B for Example 5C and Example 3A, respectively, in Example 5D.MS (ESI(−)) m/e 661 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ8.79 (t, 1H),8.62 (d, 1H), 7.94 (dd, 1H), 7.88 (d, 2H), 7.57 (d, 2H), 7.37 (m, 2H),7.30-7.14 (m, 5H), 7.02 (d, 1H), 6.92 (dd, 1H), 3.76 (s, 3H), 3.67 (q,2H), 3.28 (d, 2H), 2.95 (s, 3H), 2.85 (t, 2H), 2.83 (s, 3H), 2.64 (t,2H).

EXAMPLE 438N-((4′-(hydroxymethyl)-2′-methoxy-1,1′-biphenyl-4-yl)carbonyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamideEXAMPLE 438A methyl4′-(((tert-butyl(dimethyl)silyl)oxy)methyl)-2′-methoxy-1,1′-biphenyl-4-carboxylate

A solution of Example 417A (136 mg, 0.50 mmol), tert-butyldimethylsilylchloride (91 mg, 0.60 mmol), and N,N-diisopropylethylamine (129 mg, 1.0mmol) in dichloromethane (5 mL) at room temperature was stirred for 3hours, and filtered through a pad of silica gel. The pad was rinsed withether and the combined solutions were concentrated to provide thedesired product.

EXAMPLE 438BN-((4′-(hydroxymethyl)-2′-methoxy-1,1′-biphenyl-4-yl)carbonyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

A mixture of Example 438A (0.50 mmol) and 1M LiOH (0.60 mL) in THF (2mL) was heated to 50° C., stirred for 3 hours, concentrated, dissolvedin DMF (5 mL), and treated with a mixture of Example 77B (211 mg, 0.60mmol), EDCI (193 mg, 1.0 mmol), and DMAP (50 mg). The mixture wasstirred for 16 hours, treated with 1M HF (3 mL), stirred for 3 hours,diluted with ethyl acetate (100 mL), washed sequentially with 1M HCl (10mL), water (20 mL), and brine (10 mL), dried (MgSO₄), filtered, andconcentrated. The concentrate was purified by flash columnchromatography on silica gel with 50-100% ethyl acetate/hexanes toprovide the desired product. MS (ESI(−)) m/e 592 (M−H)⁻; ¹H NMR (300MHz, DMSO-d₆) δ8.79 (t, 1H), 8.62 (d, 1H), 7.92 (dd, 1H), 7.89 (d, 2H),7.54 (d, 2H), 7.37 (m, 2H), 7.28 (m, 3H), 7.18 (tt, 1H), 7.06 (s, 1H),6.97 (d, 1H), 4.54 (s, 2H), 3.76 (s, 3H), 3.66 (q, 2H), 3.20 (t, 2H).

EXAMPLE 439N-(4-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamideEXAMPLE 439A 1-benzyl-1,2,3,6-tetrahydropyridin-4-yl trifluoroacetate

The desired product was prepared by substituting 1-benzyl-4-piperidonefor 4-tert-butylcyclohexanone in Example 5A.

EXAMPLE 439B methyl 4-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)benzoate

The desired product was prepared by substituting Example 439A forExample 5A in Example 5B. MS (DCI (+)) m/e 308 (M+H)⁺.

EXAMPLE 439CN-(4-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 439B forExample 230B in Example 230C. MS (ESI(−)) m/e 627 (M−H)⁻; ¹H NMR (300MHz, DMSO-d₆) δ8.55 (br t, 1H), 8.50 (d, 1H), 7.92 (dd, 1H), 7.85 (d,2H), 7.55-7.15 (m, 12H), 7.00 (d, 1H), 6.35 (s, 1H), 4.21 (s, 2H), 3.65(m, 2H), 3.52-2.50 (m, 10H).

EXAMPLE 440N-(4-(1-butyl-1H-benzimidazol-5-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamideEXAMPLE 440A 5-bromo-1-butyl-1H-benzimidazole

The desired product was prepared by substituting Example 166B and formicacid for Example 343A and valeric acid, respectively, in Example 343B.

EXAMPLE 440BN-(4-(1-butyl-1H-benzimidazol-5-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 440A andExample 214E for 6-bromoindole and 4-(dihydroxyboryl)benzoic acid,respectively, in Example 4A. MS (ESI) m/e 628, 630 (M−H)⁻, (M+H)⁺; ¹HNMR (300 MHz, DMSO-d₆) δ0.91 (t, 3H), 1.25 (qt, 2H), 1.79 (tt, 2H), 3.28(t, 2H), 3.61 (dt, 2H), 4.27 (t, 2H), 6.99 (d, 1H), 7.19 (tt, 1H), 7.30(td, 2H), 7.39 (dd, 2H), 7.47-7.62 (m, 3H), 7.66 (t, 2H), 7.88 (dd, 1H),7.92-7.98 (m, 2H), 8.26 (s, 1H), 8.52 (d, 1H), 8.53 (t, 1H).

EXAMPLE 4412-(2-methoxy-4′-((((3-nitro-4-((2-(phenylthio)ethyl)amino)phenyl)sulfonyl)amino)carbonyl)-1,1′-biphenyl-4-yl)-N,N-dimethylacetamideEXAMPLE 441A methyl4′-(2-(dimethylamino)-2-oxoethyl)-2′-methoxy-1,1′-biphenyl-4-carboxylate

The desired product was prepared by substituting dimethylamine for1-methylpiperazine in Example 328B.

EXAMPLE 441B2-(2-methoxy-4′-((((3-nitro-4-((2-(phenylthio)ethyl)amino)phenyl)sulfonyl)amino)carbonyl)-1,1′-biphenyl-4-yl)-N,N-dimethylacetamide

The desired product was prepared by substituting Example 441A andExample 77B for Example 5C and Example 3A, respectively, in Example 5D.MS (ESI(−)) m/e 647 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ8.79 (t, 1H),8.62 (d, 1H), 7.93 (dd, 1H), 7.88 (d, 2H), 7.57 (d, 2H), 7.47 (m, 2H),7.30-7.15 (m, 5H), 6.99 (d, 1H), 6.89 (dd, 1H), 3.74 (s, 3H), 3.73 (s,2H), 3.67 (q, 2H), 3.26 (d, 2H), 3.03 (s, 3H), 2.84 (s, 3H).

EXAMPLE 4428-(4-((((4-((2-adamantylmethyl)amino)-3-nitrophenyl)sulfonyl)amino)carbonyl)phenyl)quinoline-2-carboxylicacid

The desired product was prepared by substituting Example 436A andExample 255A for Example 389A and Example 108A, respectively, in Example389B. MS (ESI(−)) m/e 639 (M−H)⁻; ¹H NMR (400 MHz, DMSO-d₆) δ8.69 (d,1H), 8.62 (d, 1H), 8.57 (t, 1H), 8.14 (d, 2H), 7.97 (m, 3H), 7.93 (dd,1H), 7.87 (d, 2H), 7.73 (dd, 1H), 7.36 (d, 1H), 3.19 (d, 2H), 1.98 (m,3H), 1.72-1.55 (m, 12H).

EXAMPLE 4434-((2-(benzyloxy)-1-((phenylthio)methyl)ethyl)amino)-N-((4′-fluoro-1,1′-biphenyl-4-yl)carbonyl)-3-nitrobenzenesulfonamideEXAMPLE 443A methyl O-benzyl-N-(tert-butoxycarbonyl)serinate

A mixture of BOC-DL-Ser-OMe (434 mg, 2.0 mmol), benzyl bromide (513 mg,3.0 mmol), and silver oxide (695 mg, 3.0 mmol) in dichloromethane (10mL) at room temperature was stirred for 2 days, filtered, andconcentrated. The concentrate was purified by flash columnchromatography on silica gel with 20% ethyl acetate/hexanes to providethe desired product. MS (ESI(−)) m/e 308 (M−H)⁻.

EXAMPLE 443B tert-butyl 2-(benzyloxy)-1-(hydroxymethyl)ethylcarbamate

The desired product was prepared by substituting Example 443A forExample 175A in Example 175B. MS (ESI(−)) m/e 280 (M−H)⁻.

EXAMPLE 443C tert-butyl2-(benzyloxy)-1-((phenylthio)methyl)ethylcarbamate

The desired product was prepared by substituting Example 443B forExample 122A in Example 122B. MS (ESI(−)) m/e 372 (M−H)⁻.

EXAMPLE 443D4-((2-(benzyloxy)-1-((phenylthio)methyl)ethyl)amino)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 443C forExample 180A in Example 180B. MS (ESI(−)) m/e 472 (M−H)⁻.

EXAMPLE 443E4-((2-(benzyloxy)-1-((phenylthio)methyl)ethyl)amino)-N-((4′-fluoro-1,1′-biphenyl-4-yl)carbonyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 443D for forExample 1C in Example 1D. MS (ESI(−)) m/e 670 (M−H)⁻; ¹H NMR (500 MHz,DMSO-d₆) δ8.61 (d, 1H), 8.60 (d, 1H), 7.97 (d, 2H), 7.79 (dd, 1H), 7.79(m, 4H), 7.35-7.26 (m, 8H), 7.23 (m, 3H), 7.16 (m, 1H), 4.50 (s, 2H),4.27 (m, 1H), 3.73 (dd, 1 H), 3,67 (dd, 1H), 3.38 (m, 2H).

EXAMPLE 445N-((4′-(2-hydroxyethyl)-2′-methoxy-1,1′-biphenyl-4-yl)carbonyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamideEXAMPLE 445A methyl 2′-methoxy-4′-vinyl-1,1′-biphenyl-4-carboxylate

A suspension of methyltriphenylphosphonium bromide (785 mg, 2.2 mmoL) inTHF (5 mL) was treated with 1M lithium bis(trimethylsilyl)amide in THF(2.2 mL), stirred for 30 minutes, treated with a solution of Example122I (540 mg, 2.0 mmol) in THF (2 mL), stirred for 1 hour, and filteredthrough a pad of silica gel (20 g). The pad was rinsed with 1:1ether/dichlormethane and concentrated. The concentrate was purified byflash column chromatography on silica gel with 20-50%dichloromethane/hexanes to provide the desired product.

EXAMPLE 445B methyl4′-(2-hydroxyethyl)-2′-methoxy-1,1′-biphenyl-4-carboxylate

A solution of Example 445A (228 mg) and 1M borane in THF (1.2 mL) in THF(2 mL) at room temperature was stirred for 5 hours, and treatedsequentially with 2M sodium carbonate (1 mL) and 33% hydrogen peroxide(1 mL). The mixture was heated to 60° C. for 1 hour, diluted with ethylacetate (100 mL), washed with water (45 mL) and brine (10 mL), dried(MgSO₄), filtered, and concentrated. The concentrate was purified byflash column chromatography on silica gel with 20-40% ethylacetate/hexanes to provide the desired product.

EXAMPLE 445C methyl4′-(2-((tert-butyl(dimethyl)silyl)oxy)ethyl)-2′-methoxy-1,1′-biphenyl-4-carboxylate

The desired product was prepared by substituting Example 445B forExample 417A in Example 438A.

EXAMPLE 445DN-((4′-(2-hydroxyethyl-2′-methoxy-1,1′-biphenyl-4-yl)carbonyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 445C forExample 438A in Example 438B. MS (ESI(−)) m/e 606 (M−H)⁻; ¹H NMR (300MHz, DMSO-d₆) δ8.64 (t, 1H), 8.56 (d, 1H), 7.90 (dd, 1H), 7.88 (d, 2H),7.46 (d, 2H), 7.38 (m, 2H), 7.30 (m, 2H), 7.20 (m, 2H), 7.10 (d, 1H),6.97 (d, 1H), 6.88 (dd, 1H), 4.65 (t, 1H), 3.76 (s, 3H), 3.64 (m, 4H),3.20 (t, 2H), 2.75 (t, 2H).

EXAMPLE 446N-((2′-methoxy-4′-(2-methoxyethyl)-1,1′-biphenyl-4yl)carbonyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamideEXAMPLE 446A methyl2′-methoxy-4′-(2-methoxyethyl)-1,1′-biphenyl-4-carboxylate

The desired product was prepared by substituting Example 445B forExample 417A in Example 417B.

EXAMPLE 446BN-((2′-methoxy-4′-(2-methoxyethyl)-1,1′-biphenyl-4-yl)carbonyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 446A andExample 77B for Example 5C and Example 3A, respectively, in Example 5D.MS (ESI(−)) m/e 620 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ8.64 (t, 1H),8.56 (d, 1H), 7.90 (dd, 1H), 7.88 (d, 2H), 7.46 (d, 2H), 7.38 (m, 2H),7.30 (m, 2H), 7.20 (m, 2H), 7.10 (d, 1H), 6.97 (d, 1H), 6.88 (dd, 1H),3.78 (s, 3H), 3.64 (m, 4H), 3.44 (m, 2H), 3.28 (t, 23H), 3.13 (m, 2H),3.08 (m, 2H), 2.69 (m, 2H), 2.03 (m, 2H), 1.53 (m, 2H).

EXAMPLE 447N,N-diisopropyl-4-(4-((((3-nitro-4-((2-(phenylthio)ethyl)amino)phenyl)sulfonyl)amino)carbonyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxamide

The desired product was prepared by substituting diisopropylcarbamylchloride for 4-morpholinecarbonyl chloride in Example 317. MS (ESI(−))m/e 664 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ8.78 (br t, 1H), 8.60 (d,1H), 7.92 (dd, 1H), 7.85 (d, 2H), 7.40-7.15 (m, 8H), 6.20 (d, 1H), 3.70(m, 2H), 2.40-1.20 (m, 10H), 0.85 (2s, 12H).

EXAMPLE 448N-(4-(2-butyl-1-(cyclohexylmethyl)-1H-benzimidazol-5-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamideEXAMPLE 448A 5-bromo-2-butyl-1-(cyclohexylmethyl)-1H-benzimidazole

The desired product was prepared by substituting Example 430A forExample 343A in Example 343B.

EXAMPLE 448B4-(2-butyl-1-(cyclohexylmethyl)-1H-benzimidazol-5-yl)benzoic acid

The desired product was prepared by substituting Example 448A for6-bromoindole in Example 4A.

EXAMPLE 448CN-(4-(2-butyl-1-(cyclohexylmethyl)-1H-benzimidazol-5-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 448B andExample 77B for Example 1B and Example 1C, respectively, in Example 1D.MS (ESI) m/e 724, 726 (M−H)⁻, (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ0.96(t, 3H), 1.03-1.55 (m, 5H), 1.45 (qt, 2H), 1.47-1.73 (m, 5H) 1.82 (m,3H), 2.86 (t, 2H), 3.27 (t, 2H), 3.63 (dt, 2H), 4.06 (d, 2H), 7.08 (d,1H), 7.19 (tt, 1H), 7.29 (td, 2H), 7.39 (dd, 2H), 7.53 (dd, 1H), 7.60(d, 1H), 7.71 (d, 2H), 7.86 (s, 1H), 7.92 (dd, 1H), 7.96 (d, 2H), 8.56(d, 1H), 8.53 (t, 1H).

EXAMPLE 449N-(4-(5-chloropyridin-2-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting 2,4-dichloropyridinefor 2,8-bistrifluoromethyl-3-chloroquinoline in Example 319. MS(APCI(+)) m/e 569(M+H)⁺; (APCI(−)) m/e 567(M−H)⁻; ¹H NMR (500 MHz,DMSO-d₆) δ8.78 (t, 1H), 8.74 (d, 1H), 8.63 (d, 1H), 8.19 (d, 2H), 8.15(d, 1H), 8.05 (dd, 1H), 7.99 (d, 2H), 7.94 (dd, 1H), 7.36 (dt, 2H), 7.27(td, 2H), 7.21 (d, 1H), 7.18 (tt, 1H), 3.68 (q, 2H), 3.25 (m, 2H).

EXAMPLE 450N-((2′-methoxy-4′-(3-morpholin-4-ylpropyl)-1,1′-biphenyl-4-yl)carbonyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 122O andExample 77B for Example 1B and Example 1C, respectively, in Example 1D.MS (ESI(−)) m/e 691 (M−H)⁻; ¹H NMR (500 MHz, DMSO-d₆) δ10.15 (br s, 1H),8.79 (t, 1H), 8.63 (d, 1H), 7.93 (dd, 1H), 7.88 (d, 2H), 7.57 (d, 2H),7.37 (m, 2H), 7.26 (m, 3H), 7.23 (d, 1H), 7.17 (tt, 1H), 7.02 (d, 1H),6.92 (dd, 1H), 3.76 (s, 2H), 3.75 (s, 3H), 3.67 (q, 2H), 3.56-3.52 (m,6H), 3.47 (m, 2H), 3.26 (d, 2H).

EXAMPLE 451N-((4′-(3-hydroxypropyl)-2′-methoxy-1,1′-biphenyl-4-yl)carbonyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamideEXAMPLE 451A methyl4′-(3-((tert-butyl(dimethyl)silyl)oxy)propyl)-2′-methoxy-1,1′-biphenyl-4-carboxylate

The desired product was prepared by substituting Example 431A forExample 417A in Example 438A.

EXAMPLE 451B4′-(3-((tert-butyl(dimethyl)silyl)oxy)propyl)-2′-methoxy-1,1′-biphenyl-4-carboxylicacid

A mixture of Example 451A (828 mg, 2.0 mmol) and 1M LiOH (3 mL) in THF(10 mL) was heated to 50° C., stirred for 3 hours, diluted with ethylacetate, washed with saturated sodium monobasic phosphate (10 mL), dried(MgSO₄), filtered, and concentrated to provide the desired product.

EXAMPLE 451CN-((4′-(3-hydroxypropyl)-2′-methoxy-1,1′-biphenyl-4-yl)carbonyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

A mixture of Example 451B (200 mg, 0.5 mmol), Example 77B (211 mg, 0.60mmol), EDCI (193 mg, 1.0 mmol), and DMAP (50 mg) at room temperature wasstirred for 16 hours, treated with 1M HF (3 mL), stirred for 3 hours,diluted with ethyl acetate (100 mL), washed sequentially with 1M HCl (10mL), water (20 mL), and brine (10 mL), dried (MgSO₄), filtered, andconcentrated. The concentrate was purified by flash columnchromatography on silica gel with 50-100% ethyl acetate/hexanes toprovide the desired product. MS (ESI(−)) m/e 620 (M−H)⁻; ¹H NMR (300MHz, DMSO-d₆) δ8.80 (t, 1H), 8.63 (d, 1H), 7.93 (dd, 1H), 7.88 (d, 2H),7.57 (d, 2H), 7.47 (m, 2H), 7.30-7.15 (m, 5H), 6.97 (d, 1H), 6.88 (dd,1H), 3.76 (s, 3H), 3.64 (m, 2H), 3.45 (t, 2H), 3.20 (t, 2H), 2.64 (t,2H), 1.75 (m, 2H).

EXAMPLE 4524-((5-amino-1-((phenylthio)methyl)pentyl)amino)-N-((4′-fluoro-1,1′-biphenyl-4-yl)carbonyl)-3-nitrobenzenesulfonamide

A mixture of Example 345D (30 mg) and 4M HCl in 1,4-dioxane (3 mL) atroom temperature was stirred for 5 hours and concentrated to provide thedesired product as the HCl salt. MS (ESI(−)) m/e 621 (M−H)⁻; ¹H NMR (400MHz, DMSO-d₆) δ8.57 (d, 1H), 8.31 (d, 1H), 7.98 (d, 2H), 7.89 (dd, 1H),7.68 (m, 4H), 7.73 (m, 3H), 7.35-7.13 (m, 7H), 4.12 (m, 1H), 3.67 (m,2H), 2.74 (m, 2H), 1.75(m, 2H), 1.53 (m, 2H), 1.40 (m, 2H).

EXAMPLE 453(3R)-3-((4-((((4′-fluoro-1,1′-biphenyl-4-yl)carbonyl)amino)sulfonyl)-2-nitrophenyl)amino)-N,N-dimethyl-4-(phenylthio)butanamide

The desired product was prepared by substituting Example 122F forExample 1C in Example 1D. MS (ESI(−)) m/e 635 (M−H)⁻; ¹H NMR (500 MHz,methanol-d₄) δ8.73 (d, 1H), 8.09 (d, 1H), 7.98 (d, 2H), 7.93 (dd, 1H),7.67 (m, 4H), 7.32 (m, 2H), 7.18 (m, 4H), 7.01 (d, 1H), 4.44 (m, 1H),3.35 (m, 2H), 2.95 (dd(1H), 2.87 (s, 3H), 2.86 (s, 3H), 2.82 (dd, 1H).

EXAMPLE 454N-(4-(2-acetyl-3-methyl-1-benzothien-5-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamideEXAMPLE 454A methyl 4-(2-acetyl-3-methyl-1-benzothien-5-yl)benzoate

The desired product was prepared by substituting1-(5-chloro-3-methyl-1-benzothien-2-yl)ethanone for5-chloro-2-methyl-1,3-in Example 54A.

EXAMPLE 454B 4-(2-acetyl-3-methyl-1-benzothien-5-yl)benzoic acid

The desired product was prepared by substituting Example 454A forExample 1A in Example 1B. MS (ESI(−)) m/e 309(M)⁻.

EXAMPLE 454CN-(4-(2-acetyl-3-methyl-1-benzothien-5-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 454B andExample 77B for Example 1B and Example 1C, respectively, in Example 1D.MS (ESI(−)) m/e 521 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ3.26 (t, 2H),3.60 (dt, 2H), 6.27 (s, 2H), 7.00 (d, 1H), 7.20 (t, 1H), 7.31 (t, 2H),7.40 (d, 2H), 7.42 (s, 2H), 7.52 (d, 2H), 7.89 (d, 1H), 7.93 (d, 2H),8.51 (d, 1H), 8.52 (t, 1H).

EXAMPLE 455 tert-butyl4-(4-((((3-nitro-4-((2-(phenylthio)ethyl)amino)phenyl)sulfonyl)amino)carbonyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylateEXAMPLE 455A tert-butyl4-((trifluoroacetyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate

The desired product was prepared by substitutingtert-butyl-4-oxo-piperidinecarboxylate for 4-tert-butylcyclohexanone inExample 5A.

EXAMPLE 455B tert-butyl4-(4-(methoxycarbonyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate

The desired product was prepared by substituting Example 455A forExample 5A in Example 5B. MS (DCI (+)) m/e 318 (M+H)⁺.

EXAMPLE 455C tert-butyl4-(4-((((3-nitro-4-((2-(phenylthio)ethyl)amino)phenyl)sulfonyl)amino)carbonyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate

A mixture of Example 455B (1 g, 3.1 mmol) and LiOH (0.264 mg 6.2 mmol)in THF (15 mL), methanol (2.5 mL), and water (1.5 mL) was heated to 50°C. for 3 hours and concentrated. The concentrate was dissolved in DMF(10 mL) and treated with a mixture of Example 77B (1.059 g, 3 mmol),EDCI (1.146 g, 6 mmol), and DMAP (1.830, 15 mmol) in dichloroethane (10mL), stirred for 16 hours, diluted with ethyl acetate (250 mL0, washedsequentially with 1N HCl (50 mL, water (100 mL) and brine (100 mL),dried (MgSO₄), filtered, and concentrated. The concentrate was purifiedby flash column chromatography on silica gel with 5%methanol/dichloromethane to provide the desired product. MS (ESI(−)) m/e637 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ8.78 (br t, 1H), 8.60 (d, 1H),7.92 (dd, 1H), 7.85 (d, 2H), 7.55 (d, 2H), 7.40-7.15 (m, 6H), 6.35 (m,1H), 4.21 (d, 2H), 3.65 (m, 2H), 3.52 (t, 2H), 3.25 (m, 4H), 1.45 (s,9H).

EXAMPLE 4563-nitro-4-((2-(phenylthio)ethyl)amino)-N-(4-((1R,4R)-1,7,7-trimethylbicyclo(2.2.1)hept-2-en-2-yl)benzoyl)benzenesulfonamide

The desired product was prepared by substituting Example 372B forExample 230B in Example 230C. MS (ESI(−)) m/e 590 (M−H)⁻; ¹H NMR (300MHz, DMSO-d₆) δ8.78 (br t, 1H), 8.60 (d, 1H), 7.92 (dd, 1H), 7.85 (d,2H), 7.40-7.15 (m, 8H), 6.20 (d, 1H), 3.70 (m, 2H), 2.40 (t, 1H), 1.95(m, 2H), 1.65 (m, 2H), 1.25 (m, 4H), 1.05 (s, 3H), 0.85 (2s, 6H).

EXAMPLE 4573-((4-((((4′-fluoro-1,1′-biphenyl-4-yl)carbonyl)amino)sulfonyl)-2-nitrophenyl)amino)-N,N-dimethyl-4-(phenylthio)butanamideEXAMPLE 457A3-((4-(aminosulfonyl)-2-nitrophenyl)amino)-N,N-dimethyl-4-(phenylthio)butanamide

The desired product was prepared by substituting Fmoc-DL-Asp(OtBu)-OHfor Fmoc-D-Asp(OtBu)-OH in Examples 122A-F.

EXAMPLE 457B3-((4-((((4′-fluoro-1,1′-biphenyl-4-yl)carbonyl)amino)sulfonyl)-2-nitrophenyl)amino)-N,N-dimethyl-4-(phenylthio)butanamide

The desired product was prepared by substituting Example 457A forExample 1C in Example 1D. MS (ESI(−)) m/e 635 (M−H)⁻; ¹H NMR (500 MHz,methanol-d₄) δ8.73 (d, 1H), 8.09 (d, 1H), 7.98 (d, 2H), 7.93 (dd, 1H),7.67 (m, 4H), 7.32 (m, 2H), 7.18 (m, 4H), 7.01 (d, 1H), 4.44 (m, 1H),3.35 (m, 2H), 2.95 (dd (1H), 2.87 (s, 3H), 2.86 (s, 3H), 2.82 (dd, 1H).

EXAMPLE 458 methylN-(4-((((4′-fluoro-1,1′-biphenyl-4-yl)carbonyl)amino)sulfonyl)-2-nitrophenyl)-S-phenylcysteinate

The desired product was prepared by substituting Example 434A forExample 1C in Example 1D. MS (ESI(−)) m/e 608 (M−H)⁻; ¹H NMR (300 MHz,DMSO-d₆) δ8.70 (d, 1H), 8.51 (d, 1H), 7.96 (d, 2H), 7.90 (dd, 1H), 7.75(m, 3H), 7.66 (d, 2H), 7.32-7.25 (m, 4H), 7.20-7.00 (m, 4H), 5.04 (m,1H), 3.70-3.57 (m, 2H), 3.59 (s, 3H).

EXAMPLE 459N-(4-(4,4-dimethylpiperidin-1-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 119C andExample 77B for Example 1B and Example 1C, respectively, in Example 1D.MS(ESI(+)) m/e 569 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ11.96 (s, 1H),8.77 (t, 1H), 8.60 (d, 1H), 7.91 (dd, 1H), 7.72 (d, 2H), 7.37 (m, 2H),7.28-7.12 (m, 4H), 6.92 (d, 2H), 3.67 (m, 1H), 3.32 (m, 6H), 1.37 (t,4H), 0.95 (s, 6H).

EXAMPLE 461N-(4-(8-azaspiro(4.5)dec-8-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 257C andExample 77B for Example 1B and Example 1C, respectively, in Example 1D.MS(ESI(+)) m/e 569 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ11.96 (s, 1H),8.77 (t, 1H), 8.51 (d, 1H), 7.88 (dd, 1H), 7.71 (d, 2H), 7.40 (m, 2H),7.30 (m, 2H), 7.18 (m, 1H), 7.06 (d, 1H), 6.85 (d, 2H), 3.62 (m, 2H),3.30 (m, 6H), 1.59 (m, 4H), 1.48 (m, 8H).

EXAMPLE 462N-((4′-fluoro-1,1′-biphenyl-4-yl)carbonyl)-4-(((1R)-3-morpholin-4-yl-3-oxo-1-((phenylthio)methyl)propyl)amino)-3-nitrobenzenesulfonamideEXAMPLE 462A4-(((1R)-3-morpholin-4-yl-3-oxo-1-((phenylthio)methyl)propyl)amino)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting morpholine fordimethylamine in Example 122F.

EXAMPLE 462BN-((4′-fluoro-1,1′-biphenyl-4-yl)carbonyl)-4-(((1R)-3-morpholin-4-yl-3-oxo-1-((phenylthio)methyl)propyl)amino)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 462A forExample 1C in Example 1D. MS (ESI(−)) m/e 677 (M−H)⁻; ¹H NMR (300 MHz,methanol-d₄) δ8.79 (d, 1H), 8.75 (d, 1H), 7.94 (m, 3H), 7.70 (m, 4H),7.30 (m, 2H), 7.24-7.13 (m, 5H), 7.01 (d, 1H), 4.50 (m, 1H), 3.62-3.52(m, 4H), 3.52-3.46 (m, 4H), 3.37 (m, 2H), 3.00 (dd (1H), 2.85 (dd, 1H).

EXAMPLE 463N-((2′-methoxy-4′-(3-morpholin-4-ylpropyl)-1,1′-biphenyl-4-yl)carbonyl)-4-(((1R)-3-morpholin-4-yl-1-((phenylthio)methyl)propyl)amino)-3-nitrobenzenesulfonamideEXAMPLE 463A4-(((1R)-3-morpholin-4-yl-1-((phenylthio)methyl)propyl)amino)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 462A forExample 122F in Example 122G.

EXAMPLE 463BN-((2′-methoxy-4′-(3-morpholin-4-ylpropyl)-1,1′-biphenyl-4-yl)carbonyl)-4-(((1R)-3-morpholin-4-yl-1-((phenylthio)methyl)propyl)amino)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 122O andExample 463A for Example 1B and Example 1C, respectively, in Example 1D.MS (ESI(−)) m/e 802 (M−H)⁻; ¹H NMR (500 MHz, methanol-d₄) δ8.71 (d, 1H),7.95 (dd, 1H), 7.90 (d, 2H), 7.52 (d, 2H), 7.29 (dd, 2H), 7.22 (d, 1H),7.14 (m, 3H), 6.96 (d, 1H), 6.95 (s, 1H), 6.89 (d, 1H), 4.15 (m, 1H),3.88 (m, 4H), 3.78 (s, 3H), 3.76 (m, 4H), 3.37 (dd, 1H), 3.24 (m, 4H),3.11 (m, 2H), 2.94-2.80 (m, 4H), 2.76 (t, 2H), 2.21 (m, 1H), 2.08 (m,3H).

EXAMPLE 464N-(4-(1-(2-morpholin-4-ylethyl)-1H-benzimidazol-5-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamideEXAMPLE 464A 4-bromo-N¹-(2-morpholin-4-ylethyl)benzene-1,2-diamine

The desired product was prepared by substituting4-(2-aminoethyl)morpholine for butylamine in Examples 166A and 166B.

EXAMPLE 464B 5-bromo-1-(2-morpholin-4-ylethyl)-1H-benzimidazole

The desired product was prepared by substituting Example 464A forExample 349A in Example 349B.

EXAMPLE 464CN-(4-(1-(2-morpholin-4-ylethyl)-1H-benzimidazol-5-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 464B andExample 214E for 6-bromoindole and 4-(dihydroxyboryl)benzoic acid,respectively, in Example 4. MS (ESI) m/e 685, 687 (M−H)⁻, (M+H)⁺, ¹H NMR(300 MHz, DMSO-d₆) δ2.46 (t, 4H), 2.72 (t, 2H), 3.28 (t, 2H), 3.55 (t,4H), 3.62 (dt, 2H), 4.39 (t, 2H), 7.02 (d, 1H), 7.02 (tt, 1H), 7.30 (t,2H), 7.40 (d, 2H), 7.58 (dd, 1H), 7.66 (d, 2H), 7.70 (d, 1H), 7.91 (dd,1H), 7.95 (d, 1H), 7.97 (d, 2H), 8.27 (s, 1H), 8.52 (t, 1H), 8.55 (d,1H).

EXAMPLE 465N-((2′-methoxy-4′-(3-morpholin-4-ylpropyl)-1,1′-biphenyl-4-yl)carbonyl)-4-(((1R)-3-(4-methylpiperazin-1-yl)-3-oxo-1-((phenylthio)methyl)propyl)amino)-3-nitrobenzenesulfonamideEXAMPLE 465A4-(((1R)-3-(4-methylpiperazin-1-yl)-3-oxo-1-((phenylthio)methyl)propyl)amino)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting 1-methylpiperidine fordimethylamine in Example 122F.

EXAMPLE 465BN-((2′-methoxy-4′-(3-morpholin-4-ylpropyl)-1,1′-biphenyl-4-yl)carbonyl)-4-(((1R)-3-(4-methylpiperazin-1-yl)-3-oxo-1-((phenylthio)methyl)propyl)amino)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 122O andExample 465A for Example 1B and Example 1C, respectively, in Example 1D.MS (ESI(−)) m/e 829 (M−H)⁻; ¹H NMR (500 MHz, methanol-d₄) δ8.71 (d, 1H),7.95 (dd, 1H), 7.90 (d, 2H), 7.52 (d, 2H), 7.29 (dd, 2H), 7.22 (d, 1H),7.14 (m, 3H), 6.96 (d, 1H), 6.95 (s, 1H), 6.89 (d, 1H), 4.40 (m, 1H),3.78 (s, 3H), 3.76 (m, 4H), 3.52 (m, 4H), 3.37 (dd, 1H), 3.20 (s, 3H),2.95 (dd, 1H), 2.68 (m, 4H), 2.58 (m, 4H), 2.50 (m, 4H), 2.18 (m, 2H),1.90 (m, 2H).

EXAMPLE 466N-(4-(4,4-dimethylpiperidin-1-yl)benzoyl)-4-(((1R)-3-(4-methylpiperazin-1-yl)-3-oxo-1-((phenylthio)methyl)propyl)amino)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 119C andExample 465A for Example 1B and Example 1C, respectively, in Example 1D.MS(ESI(+)) m/e 709 (M+H)⁺; ¹H NMR (500 MHz, methanol-d₄) δ8.71 (d, 1H),8.65 (d, 1H), 7.90 (dd, 1H), 7.77 (d, 2H), 7.31 (m, 2H), 7.17 (m, 3H),6.88 (m, 3H), 3.82 (m, 1H), 3.53 (m, 4H) 3.33 (m, 4H), 3.05 (m, 1H),2.95 (dd, 1H), 2.83 (m, 2H), 2.40 (m, 4H), 2.25 (s, 3H), 1.47 (m, 4H),0.97 (s, 6H).

EXAMPLE 4674-(((1R)-5-amino-1-(phenylsulfonyl)methyl)amino)-N-((2′-methoxy-4′-(3-morpholin-4-ylpropyl)-1,1′-biphenyl-4-yl)carbonyl)-3-nitrobenzenesulfonamide

A mixture of Example 194 (100 mg) in acetonitrile (5 mL) and saturatedaqueous sodium periodate (3 mL) at room temperature was stirred for 3days and concentrated. The concentrate was purified by flash columnchromatography on silica gel with 0-3% concentrated aqueous ammonia in1:1 isopropanol/dichloromethane, and purified a second time by reversephase column chromatography with 0-100% acetonitrile/water to providethe desired product. MS (ESI(−)) m/e 792 (M−H)⁻; ¹H NMR (500 MHz,DMSO-d₆) δ8.41 (1H), 7.92 (d, 2H), 7.84 (m, 2H), 7.65 (d, 2H), 7.56 (m,3H), 7.41 (m, 3H), 7.20 (d, 1H), 6.96 (d, 1H), 6.95 (s, 1H), 6.87 (d,1H), 4.24 (m, 1H), 4.05 (dd, 1H), 3.63 (m, 4H), 2.72 (m, 2H), 2.63 (t,2H), 1.86 (m, 2H), 1.70 (m, 2H), 1.48 (2H), 1.33 (m, 2H).

EXAMPLE 468N-(4-(5-(3-morpholin-4-ylpropyl)quinolin-8-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamideEXAMPLE 468A methyl4-(5-(3-morpholin-4-yl-3-oxopropyl)quinolin-8-yl)benzoate

The desired product was prepared by substituting morpholine for1-methylpiperazine in Example 201J.

EXAMPLE 468B methyl 4-(5-(3-morpholin-4-ylpropyl)quinolin-8-yl benzoate

The desired product was prepared by substituting Example 468A forExample 362A in Example 248A.

EXAMPLE 468C 4-(5-(3-morpholin-4-ylpropyl)quinolin-8-yl)benzoic acid

The desired product was prepared by substituting Example 468B forExample 1A in Example 1B.

EXAMPLE 468DN-(4-(5-(3-morpholin-4-ylpropyl)quinolin-8-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 468C andExample 77B for Example 1B and Example 1C, respectively, in Example 1D.MS (ESI) m/e 710, 712 (M−H)⁻, (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ2.02(m, 2H), 2.98 (m, 4H), 3.15 (t, 2H), 3.28 (t, 2H), 3.31 (t, 2H), 3.63(dt, 2H), 3.72 (m, 4H), 7.06 (d, 1H), 7.20 (tt, 1H), 7.31 (tt, 2H), 7.40(dt, 2H), 7.54-7.64 (m, 4H), 7.71 (d, 1H), 7.92 (dd, 1H), 7.96 (d, 2H),8.56 (d, 1H), 8.61 (dd, 1H), 8.90 (dd, 1H).

EXAMPLE 469 tert-butyl1′-(4-((((3-nitro-4-((2-(phenylthio)ethyl)amino)phenyl)sulfonyl)amino)carbonyl)phenyl)-4,4′-bipiperidine-1-carboxylate

The desired product was prepared by substituting4-(1′-(tert-butoxycarbonyl)-4,4′-bipiperidin-1-yl)benzoic acid andExample 77B for Example 1B and Example 1C, respectively, in Example 1D.MS (ESI(−)) m/e 722 (M−H)⁻; ¹H NMR (500 MHz, DMSO-d₆) δ8.72 (t, 1H),8.58 (d, 1H), 7.90 (dd, 1H), 7.72 (d, 2H), 7.37 (d, 2H), 7.25 (t, 2H),7.19-7.14 (m, 2H), 6.89 (d, 2H), 3.93 (br t, 4H), 3.66 (q, 2H), 3.28 (t,2H), 2.74 (t, 2H), 2.66-2.54 (m, 2H), 1.68 (dd, 4H), 1.38 (s, 9H),1.24-1.17 (m, 4H), 1.07-0.96 (m, 2H).

EXAMPLE 4703-nitro-N-(4-(4-(phenylsulfonyl)piperazin-1-yl)benzoyl)-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting benzenesulfonylchloride for 2-methoxyethyl chloroformate in Example 325. MS (ESI(−))m/e 680 (M−H)⁻; ¹H NMR (500 MHz, DMSO-d₆) δ12.01 (s, 1H), 8.75 (t, 1H),8.59 (d, 1H), 7.90 (dd, 1H), 7.78-7.63 (m, 7H), 7.36 (d, 2H), 7.25 (t,2H), 7.19-7.14 (m, 2H), 6.91 (d, 2H), 3.66 (q, 2H), 3.39-3.42 (m, 4H),3.28 (t, 2H), 3.01-2.97 (m, 4H).

EXAMPLE 4714-(((1R)-5-((aminocarbonyl)amino)-1-((phenylthio)methyl)pentyl)amino)-N-(4-(8-azaspiro(4.5)dec-8-yl)benzoyl)-3-nitrobenzenesulfonamide

A solution of Example 287 (60 mg, 0.1 mmol) and potassium cyanate (20mg, 0.25 mmol) in methanol (1 mL) was stirred at 55° C. for 1.5 hours,cooled to room temperature, treated with water, and extracted withdichloromethane. The combined extracts were washed with saturated sodiumbicarbonate, dried (MgSO₄), filtered, and concentrated. The concentratewas purified by reverse phase HPLC with 0-100% acetonitrile/watercontaining 0.1% TFA to provide the desired product. MS (ESI(+)) m/e 709(M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ11.97 (s, 1H), 8.53 (d, 1H), 8.32 (d,1H), 7.85 (dd, 1H), 7.73 (d, 2H), 7.25-7.10 (m, 6H), 6.93 (d, 2H), 5.90(s, 1H), 4.10 (m, 1H), 3.34 (m, 6H), 2.91 (t, 2H), 1.75 (m, 2H), 1.59(m, 4H), 1.42 (m, 8H), 1.34 (m, 4H).

EXAMPLE 472 tert-butyl4-((4-(((4-(8-azaspiro(4.5)dec-8-yl)benzoyl)amino)sulfonyl)-2-nitrophenyl)amino)-4-((phenylthio)methyl)piperidine-1-carboxylateEXAMPLE 472A tert-butyl4-(((9H-fluoren-9-ylmethoxy)carbonyl)amino)-4-(hydroxymethyl)piperidine-1-carboxylate

The desired product was prepared by substituting1-(tert-butoxycarbonyl)-4-(((9H-fluoren-9-ylmethoxy)carbonyl)amino)piperidine-4-carboxylicacid for Fmoc-D-Asp(OtBu)-OH in Example 122A. MS (ESI) m/e 451, 453(M−H)⁻, (M+H)⁺.

EXAMPLE 472B tert-butyl4-((4-(aminosulfonyl)-2-nitrophenyl)amino)-4-((hydroxymethyl)piperidine-1-carboxylate

The desired product was prepared by substituting Example 472A forExample 122B in Example 122D. MS (ESI(−)) m/e 429 (M−H)⁻.

EXAMPLE 472C tert-butyl4-((4-(aminosulfonyl)-2-nitrophenyl)amino)-4-((hydroxymethyl)piperidine-1-carboxylate

The desired product was prepared by substituting Example 472B forN-(tert-butoxycarbonyl)-L-serine methyl ester in Example 133A. MS(ESI(−)) m/e 521 (M−H)⁻.

EXAMPLE 472D tert-butyl4-((4-(((4-(8-azaspiro(4.5)dec-8-yl)benzoyl)amino)sulfonyl)-2-nitrophenyl)amino)-4-((phenylthio)methyl)piperidine-1-carboxylate

The desired product was prepared by substituting Example 472C andExample 257C for Example 1C and Example 1B, respectively, in Example 1D.MS (ESI) m/e 762, 764 (M−H)⁻, (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ1.39(s, 9H), 1.41 (m, 4H), 1.48 (m, 4H), 1.59 (m, 4H), 1.79 (dt, 2H), 2.22(br d, 2H), 2.99 (m, 2H), 3.21 (m, 4H), 3.61 (s, 2H), 3.72 (br d, 2H),6.81 (d, 2H), 6.95 (m, 1H), 7.02 (td, 2H), 7.21 (m, 3H), 7.74 (d, 2H),7.80 (dd, 1H), 8.24 (br s, 1H), 8.41 (d, 1H).

EXAMPLE 473N-(4-(5-(3-(4-methylpiperazin-1-yl)propyl)quinolin-8-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamideEXAMPLE 473A methyl4-(5-(3-(4-methylpiperazin-1-yl)propyl)quinolin-8-yl)benzoate

The desired product was prepared by substituting Example 201J forExample 362A in Example 248A.

EXAMPLE 473B4-(5-(3-(4-methylpiperazin-1-yl)propyl)quinolin-8-yl)benzoic acid

The desired product was prepared by substituting Example 473A forExample 1A in Example 1B.

EXAMPLE 473CN-(4-(5-(3-(4-methylpiperazin-1-yl)propyl)quinolin-8-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 473B andExample 77B for Example 1B and Example 1C, respectively, in Example 1D.MS (ESI) m/e 723, 725 (M−H)⁻, (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ1.89(m, 2H), 2.28 (s, 3H), 2.50 (m, 8H), 3.12 (t, 2H), 3.27 (t, 2H), 3.29(t, 2H), 3.61 (dt, 2H), 6.98 (d, 1H), 7.20 (tt, 1H), 7.32 (tt, 2H), 7.41(dd, 2H), 7.52-7.61 (m, 4H), 7.68 (d, 2H), 7.89 (dd, 1H), 7.96 (d, 2H),8.52 (d, 1H), 8.58 (dd, 1H), 8.89 (dd, 1H).

EXAMPLE 474N-((2′-methoxy-4′-(3-morpholin-4-ylpropyl)-1,1′-biphenyl-4-yl)carbonyl)-3-nitro-4-((4-((phenylthio)methyl)piperidin-4-yl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 472C andExample 122O for Example 1C and Example 1B, respectively, in Example 1D.The product was treated with TFA (5 mL), stirred for 90 minutes,concentrated, and concentrated again to provide the desired product. MS(ESI) m/e 758, 760 (M−H)⁻, (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ1.89-2.08(m, 4H), 2.65 (dt, 2H), 3.00 (m, 2H), 3.22 (br d, 2H), 3.65 (s, 2H),3.74 (m, 4H), 3.76 (s, 3H), 6.88 (d, 1H), 6.96 (s, 1H), 7.05 (m, 2H),7.23 (m, 4H), 7.41 (d, 2H), 7.85 (dd, 1H), 7.91 (d, 2H), 8.14 (s, 1H),8.42 (d, 1H).

EXAMPLE 4754-(((1R)-3-(dimethylamino)-1-((phenylthio)methyl)propyl)amino)-N-(4-(3,3-dimethylpyrrolidin-1-yl)benzoyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 122G andExample 247C for Example 1C and Example 1B, respectively, in Example 1D.MS (ESI(+)) m/e 626 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ11.92 (s, 1H),9.42 (s, 1H), 8.55 (d, 1H), 8.30 (d, 1H), 7.87 (dd, 1H), 7.73 (d, 2H),7.25-7.10 (m, 6H), 6.50 (d, 2H), 4.18 (m, 1H), 3.40 (m, 4H), 3.15 (m,2H), 3.07 (s, 2H), 2.74 (d, 6H), 2.14 (m, 2H), 1.77 (t, 2H), 1.08 (s,6H).

EXAMPLE 4764-(((1R)-3-(dimethylamino)-1-((phenylthio)methyl)propyl)amino)-N-(4-(4-ethyl-4-methylpiperidin-1-yl)benzoyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 122G andExample 123C for Example 1C and Example 1B, respectively, in Example 1D.MS (ESI(+)) m/e 654 (M+H)⁺; ¹H NMR(500 MHz, DMSO-d₆) δ12.01 (s, 1H),9.41 (s, 1H), 8.55 (d, 1H), 8.31 (d, 1H), 7.87 (dd, 1H), 7.73 (d, 2H),7.25-7.10 (m, 6H), 6.93 (d, 2H), 4.17 (m, 1H), 3.45 (m, 2H), 3.40 (d,2H), 3.26-3.10 (m, 6H), 2.74 (d, 6H), 2.14 (m, 2H), 1.38 (m, 4H), 1.28(m, 2H), 0.90 (s, 3H), 0.80 (t, 3H).

EXAMPLE 477N-(4-(8-azaspiro(4.5)dec-8-yl)benzoyl)-4-(((1R)-5-(dimethylamino)-1-((phenylsulfinyl)methyl)pentyl)amino)-3-nitrobenzenesulfonamide

A solution of Example 124F (30 mg, 0.04 mmol) and sodium periodate (46mg, 0.22 mmol) in acetonitrile (0.5 mL), dichloromethane (0.5 mL), andwater (0.5 mL) was stirred at room temperature for 24 hours, treatedwith water, and extracted with dichloromethane. The combined extractswere dried (MgSO₄), filtered, and concentrated. The concentrate waspurified by flash column chromatography on silica gel with 80% ethylacetate/10% water/10% formic acid to provide the desired product. MS(ESI(+)) m/e 710 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ8.50 (d, 0.5H), 8.40(d, 0.5H), 8.35 (d, 0.5H), 8.21 (s, 1H), 7.94 (d, 0.5H), 7.90 (dd,0.5H), 7.82 (dd, 0.5H), 7.71 (d, 2H), 7.70 (d, 1H), 7.55 (m, 2H), 7.40(m, 1H), 7.20 (m, 1H), 6.80 (d, 2H), 2.29 (m, 1H), 2.18 (d, 6H), 1.91(s, 6H), 1.68 (m, 1H), 1.59 (m, 4H), 1.49 (m, 4H), 1.45-1.30 (m, 6H).

EXAMPLE 478N˜1˜-((5R)-5-((4-(((4-(8-azaspiro(4.5)dec-8-yl)benzoyl)amino)sulfonyl)-2-nitrophenyl)amino)-6-(phenylthio)hexyl)-N˜2˜,N˜2˜-dimethylglycinamide

A mixture of Example 287 (33 mg, 0.05 mmol), N,N-dimethyglycine (10.3mg, 0.10 mmol), EDCI (20 mg, 0.10 mmol) and HOBT (20 mg, 0.15 mmol) inDMA (0.6 mL) and dichloroethane (0.3 mL) at room temperature was stirredfor 18 hours and concentrated. The concentrate was dissolved in 1:1DMSO/methanol (1 mL) and loaded on a Nova-Pak HR C-18, 6 μM, 60A, 40×100mm preparative HPLC column (eluted with 10-95% acetonitrile/watercontaining 0.1% TFA). The purified compound was dissolved in 1:1dichloromethane/methanol (1 mL), treated with 2M HCl in diethyl ether (1mL), and concentrated to provide the hydrochloride salt. MS (ESI) m/e751.3, 749.4 (M+H)⁺, (M−H)⁻; ¹H NMR (500 MHz, DMSO-d₆) δ8.53 (d, 1H),8.41 (m, 1H), 8.29 (d, 1H), 7.86 (dd, 1H), 7.73 (d, 2H), 7.25-7.09 (m,5H), 6.92 (d, 2H), 4.12 (m, 1H), 3.80 (s, 2H), 3.34 (m, 4H), 3.10 (d,2H), 2.75 (s, 6H), 1.78 (m, 2H), 1.60 (m, 4H), 1.52-1.34 (m, 12H).

EXAMPLE 479N-((5R)-5-((4-(((4-(8-azaspiro(4.5)dec-8-yl)benzoyl)amino)sulfonyl)-2-nitrophenyl)amino)-6-(phenylthio)hexyl)cyclopropanecarboxamide

The desired product was prepared by substituting cyclopropanecarboxylicacid for N,N-dimethyglycine in Example 478. MS (ESI) m/e 734.3, 732.4(M+H)⁺, (M−H)⁻, ¹H NMR (500 MHz, DMSO-d₆) δ8.53 (d, 1H), 8.30 (d, 1H),7.93 (m, 1H), 7.84 (dd, 1H), 7.73 (d, 2H), 7.25-7.09 (m, 5H), 6.92 (d,2H), 4.12 (m, 1H), 3.34 (m, 4H), 3.01 (m, 2H), 1.78 (m, 2H), 1.60 (m,4H), 1.52-1.34 (m, 12H), 0.61-0.56 (m, 5H).

EXAMPLE 480(4R)-4-((4-((((2′-methoxy-4′-(3-morpholin-4-ylpropyl)-1,1′-biphenyl-4-yl)carbonyl)amino)sulfonyl)-2-nitrophenyl)amino)-N,N-dimethyl-5-(phenylthio)pentanamideEXAMPLE 480A tert-butyl(2E,4R)-4-((tert-butoxycarbonyl)amino)-5-(phenylthio)pent-2-enoate

Example 134A (5.74 g, 20.4 mmol) in THF (25 mL) at 0° C. was treatedwith a solution of (tert-butoxycarbonylmethylene)triphenylphosphorane(8.47 g, 22.5 mmol) in THF (25 mL), warmed to room temperature, stirredfor 90 minutes, treated with hexanes (50 mL), filtered through a pad ofsilica gel, and concentrated. The concentrate was purified by flashcolumn chromatography on silica gel with 15% ethyl acetate/hexanes toprovide the desired product. MS (ESI(−)) m/e 378 (M−H)⁻.

EXAMPLE 480B (4R)-4-((tert-butoxycarbonyl)amino)-5-(phenylthio)pentanoicacid

A mixture of Example 480A (5 g, 13.2 mmol) and Wilkinson's catalyst (1g) in tolune (125 mL) was stirred under H₂ at 60° C. for 18 hours,cooled, filtered through silica gel, and concentrated. The concentratewas dissolved in 3:1:1 THF/water/MeOH (150 mL), treated with with a10-fold excess of LiOH, and stirred for 24 hrs. The mixture was pouredinto saturated NaH₂PO₄ (200 mL) and extracted three times with ethylacetate (200 mL). The combined extracts were washed with brine, dried(Na₂SO₄), filtered, and concentrated to provide the desired product. MS(ESI) m/e 324, 326 (M−H)⁻, (M+H)⁺.

EXAMPLE 480Ctert-butyl(1R)-4-(dimethylamino)-4-oxo-1-((phenylthio)methyl)butylcarbamate

The desired product was prepared by substituting Example 480B forExample 122E in Example 122F. MS (ESI) m/e 351, 353 (M−H)⁻, (M+H)⁺.

EXAMPLE 480D(4R)-4-((4-(aminosulfonyl)-2-nitrophenyl)amino)-N,N-dimethyl-5-(phenylthio)pentanamide

The desired product was prepared by substituting Example 480C forExample 133A in Examples 133B and 133C. MS (ESI) m/e 451, 453 (M−H)⁻,(M+H)⁺.

EXAMPLE 480E(4R)-4-((4-((((2′-methoxy-4′-(3-morpholin-4-ylpropyl)-1,1′-biphenyl-4-yl)carbonyl)amino)sulfonyl)-2-nitrophenyl)amino)-N,N-dimethyl-5-(phenylthio)pentanamide

The desired product was prepared by substituting Example 480D andExample 122O for Example 1C and Example 1B, respectively, in Example 1D.MS (ESI) m/e 788, 790 (M−H)⁻, (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ1.78(m, 2H), 1.95 (m, 2H), 2.35 (m, 2H), 2.40 (t, 4H), 2.62 (t, 2H), 2.82(s, 3H), 2.96 (s, 3H), 3.30 (dd, 1H), 3.36 (dd, 1H), 3.58 (t, 4H), 3.76(s, 3H), 4.07 (m, 1H), 6.85 (d, 1H), 6.95 (d, 2H), 7.18 (t, 2H), 7.23(t, 2H), 7.31 (d, 2H), 7.40 (d, 2H), 7.82 (dd, 1H), 7.90 (d, 2H), 7.95(d, 1H), 8.15 (d, 1H), 8.48 (d, 1H).

EXAMPLE 481N-((2′-methoxy-4′-(3-morpholin-4-ylpropyl)-1,1′-biphenyl-4-yl)carbonyl)-4-(((1R)-3-(4-methylpiperazin-1-yl)-1-((phenylthio)methyl)propyl)amino)-3-nitrobenzenesulfonamideEXAMPLE 481A4-(((1R)-3-(4-methylpiperazin-1-yl)-1-((phenylthio)methyl)propyl)amino)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 465A forExample 122F in Example 122G. MS (ESI(+)) m/e 480 (M+H)⁺.

EXAMPLE 481BN-((2′-methoxy-4′-(3-morpholin-4-ylpropyl)-1,1′-biphenyl-4-yl)carbonyl)-4-(((1R)-3-(4-methylpiperazin-1-yl)-1-((phenylthio)methyl)propyl)amino)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 481A andExample 122O for Example 1C and Example 1B, respectively, in Example 1D.MS (ESI) m/e 815, 817 (M−H)⁻, (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ1.52(m, 2H), 1.82 (m, 2H), 2.21 (m, 2H), 2.40 (t, 4H), 2.48 (t, 2H), 2.80(m, 4H), 3.04 (m, 4H), 2.98 (dd, 1H), 3.05 (dd, 1H), 3.53 (s, 3H), 3.58(t, 4H), 3.62 (s, 3H), 3.91 (m, 1H), 6.65 (d, 1H), 6.78 (m, 2H), 6.95(t, 1H), 6.99 (m, 3H), 7.07 (d, 2H), 7.20 (d, 2H), 7.62 (dd, 1H), 7.67(d, 2H), 8.05 (d, 1H), 8.26 (d, 1H).

EXAMPLE 4823-(2-methoxy-4′-((((4-(((1R)-3-(4-methylpiperazin-1-yl)-1-((phenylthio)methyl)propyl)amino)-3-nitrophenyl)sulfonyl)amino)carbonyl)-1,1′-biphenyl-4-yl)-N,N-dimethylpropanamideEXAMPLE 482A4′-(3-(dimethylamino)-3-oxopropyl)-2′-methoxy-1,1′-biphenyl-4-carboxylicacid

The desired product was prepared by substituting Example 427A forExample 1A in Example 1B.

EXAMPLE 482B3-(2-methoxy-4′-((((4-(((1R)-3-(4-methylpiperazin-1-yl)-1-((phenylthio)methyl)propyl)amino)-3-nitrophenyl)sulfonyl)amino)carbonyl)-1,1′-biphenyl-4-yl)-N,N-dimethylpropanamide

The desired product was prepared by substituting Example 482A andExample 481A for Example 1B and Example 1C, respectively, in Example 1D.MS (ESI) m/e 787, 789 (M−H)⁻, (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ1.90(m, 2H), 2.50 (m, 2H), 2.64 (m, 4H), 2.71 (t, 2H), 2.82 (s, 3H), 2.84(m, 2H), 2.95 (s, 3H), 3.00 (dd, 2H), 3.34 (s, 3H), 3.36 (m, 4H), 3.76(s, 3H), 4.18 (m, 1H), 5.21 (t, 1H), 6.90 (d, 1H), 7.01 (s, 1H), 7.14(m, 2H), 7.21 (m 3H), 7.29 (d, 2H), 7.49 (d, 2H), 7.90 (d, 2H), 8.25 (d,1H), 8.52 (d, 1H).

EXAMPLE 4833-(2-methoxy-4′-((((4-(((1R)-3-(4-methylpiperazin-1-yl)-3-oxo-1-((phenylthio)methyl)propyl)amino)-3-nitrophenyl)sulfonyl)amino)carbonyl)-1,1′-biphenyl-4-yl)-N,N-dimethylpropanamide

The desired product was prepared by substituting Example 482A andExample 465A for Example 1B and Example 1C, respectively, in Example 1D.MS (ESI) m/e 801, 803 (M−H)⁻, (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ2.62(m, 4H), 2.63 (t, 2H), 2.76 (dd, 1H), 2.81 (m, 2H), 2.82 (s, 3H), 2.95(s, 3H), 3.00 (m, 2H), 3.31 (s, 3H), 3.36 (m, 4H), 3.40 (m, 1H), 3.76(s, 3H), 4.34 (m, 1H), 6.83 (d, 1H), 6.99 (s, 1H), 7.19 (t, 2H), 7.25(t, 2H), 7.32 (d, 1H), 7.39 (d, 2H), 7.59 (d, 1H), 7.80 (d, 1H), 7.88(d, 2H), 7.95 (d, 1H), 8.46 (d, 1H), 8.55 (d, 1H).

EXAMPLE 4844-(((1R)-4-(dimethylamino)-1-((phenylthio)methyl)butyl)amino)-N-((2′-methoxy-4′-(3-(4-methylpiperazin-1-yl)propyl)-1,1′-biphenyl-4-yl)carbonyl)-3-nitrobenzenesulfonamideEXAMPLE 484A2′-methoxy-4′-(3-(4-methylpiperazin-1-yl)propyl)-1,1′-biphenyl-4-carboxylicacid

The desired product was prepared by substituting Example 248A forExample 1A in Example 1B.

EXAMPLE 484B4-(((1R)-4-(dimethylamino)-1-((phenylthio)methyl)butyl)amino)-N-((2′-methoxy-4′-(3-(4-methylpiperazin-1-yl)propyl)-1,1′-biphenyl-4-yl)carbonyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 484A andExample 489A for Example 1B and Example 1C, respectively, in Example 1D.MS (ESI) m/e 787, 789 (M−H)⁻, (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ1.53(m, 4H), 1.75 (m, 2H), 2.18 (s, 3H), 2.26 (s, 6H), 2.38 (m, 4H), 2.60(t, 2H), 2.98 (m, 8H), 3.74 (s, 3H), 4.02 (m, 1H), 5.82 (m, 2H), 6.85(d, 1H), 6.93 (s, 1H), 6.95 (d, 1H), 7.17 (dd, 2H), 7.25 (td, 2H), 7.33(dt, 2H), 7.38 (d, 2H), 7.82 (dd, 1H), 7.88 (d, 2H), 8.15 (d, 1H), 8.46(d, 1H).

EXAMPLE 485N-(4-(4-ethyl-4-methoxypiperidin-1-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamideEXAMPLE 485A tert-butyl 4-ethyl-4-methoxypiperidine-1-carboxylate

The desired product was prepared by substituting Example 495A forExample 494A in Example 494B.

EXAMPLE 485B 4-ethyl-4-methoxypiperidine

The desired product was prepared by substituting Example 485A forExample 494B in Example 494C.

EXAMPLE 485C tert-butyl 4-(4-ethyl-4-methoxypiperidin-1-yl)benzoate

The desired product was prepared by substituting Example 485B forExample 494C in Example 494D.

EXAMPLE 485D 4-(4-ethyl-4-methoxypiperidin-1-yl)benzoic acid

The desired product was prepared by substituting Example 485C forExample 493A in Example 493B.

EXAMPLE 485EN-(4-(4-ethyl-4-methoxypiperidin-1-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 481D andExample 77B for Example 1B and Example 1C, respectively, in Example 1D.MS(ESI(+)) m/e 599 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ11.98 (s, 1H),8.78 (t, 1H), 8.60 (d, 1H), 7.91 (dd, 1H), 7.73 (d, 2H), 7.37 (d, 2H),7.28 (m, 2H), 7.18 (m, 2H), 6.93 (d, 2H), 3.65 (m, 4H), 3.28 (t, 2H),3.07 (m, 5H), 1.75 (m, 2H), 1.43 (m, 4H), 0.77 (t, 3H).

EXAMPLE 486N-(4-(4-(benzylsulfonyl)piperazin-1-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting benzylsulfonyl chloridefor 2-methoxyethyl chloroformate in Example 325. MS (ESI(−)) m/e 694(M−H)⁻; ¹H NMR (500 MHz, DMSO-d₆) δ12.06 (s, 1H), 8.76 (t, 1H), 8.60 (d,1H), 7.92 (dd, 1H), 7.76 (d, 2H), 7.44-7.35 (m, 7H), 7.30-7.16 (m, 4H),6.96 (d, 2H), 4.46 (s, 2H), 3.66 (q, 2H), 3.36-3.28 (m, 6H), 3.23-3.19(m, 4H).

EXAMPLE 487N-(4-(4-((4-methylphenyl)sulfonyl)piperazin-1-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting p-toluenesulfonylchloride for 2-methoxyethyl chloroformate in Example 325. MS (ESI(−))m/e 694 (M−H)⁻; ¹H NMR (500 MHz, DMSO-d₆) δ12.04 (s, 1H), 8.77 (t, 1H),8.59 (d, 1H), 7.90 (dd, 1H), 7.72-7.63 (m, 2H), 7.64 (d, 2H), 7.45 (d,2H), 7.36 (d, 2H), 7.26 (t, 2H), 7.18-7.14 (m, 2H), 6.91 (d, 2H), 3.66(q, 2H), 3.42-3.39 (m, 4H), 3.28 (t, 2H), 2.97-2.94 (m, 4H), 2.39 (s,3H).

EXAMPLE 488N-(4-(4-benzylpiperidin-1-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamideEXAMPLE 488A tert-butyl 4-(4-benzylpiperidin-1-yl)benzoate

The desired product was prepared by substituting 4-benzyl piperidine for4-hydroxy-4-phenyl piperidine in Example 493A.

EXAMPLE 488B 4-(4-benzylpiperidin-1-yl)benzoic acid

The desired product was prepared by substituting Example 488A forExample 493A in Example 493B.

EXAMPLE 488CN-(4-(4-benzylpiperidin-1-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 488B andExample 77B for Example 1B and Example 1C, respectively, in Example 1D.MS (ESI(+)) m/e 631 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ11.98 (s, 1H),8.78 (t, 1H), 8.60 (d, 1H), 7.91 (dd, 1H), 7.73 (d, 2H), 7.37 (d, 2H),7.27 (m, 4H), 7.18 (m, 5H), 6.93 (d, 2H), 3.90 (2H, m) 3.66 (q, 2H),3.28 (m, 2H), 2.78 (t, 2H), 2.53 (m, 2H), 1.77 (m, 1H), 1.63 (m, 2H),1.19 (m, 2H).

EXAMPLE 4894-(((1R)-4-(dimethylamino)-1-((phenylthio)m,ethyl)butyl)amino)-N-((2′-methoxy-4′-(2-(4-methylpiperazin-1-yl)ethyl)-1,1′-biphenyl-4-yl)carbonyl)-3-nitrobenzenesulfonamideEXAMPLE 489A4-(((1R)-4-(dimethylamin)o-1-((phenylthio)methyl)butyl)amino)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 480D forExample 122F in Example 122G. MS (ESI) m/e 437, 439 (M−H)⁻, (M+H)⁺.

EXAMPLE 489B4-(((1R)-4-(dimethylamino)-1-((phenylthio)methyl)butyl)amino)-N-((2′-methoxy-4′-(2-(4-methylpiperazin-1-yl)ethyl)-1,1′-biphenyl-4-yl)carbonyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 242B andExample 489A for Example 1B and Example 1C, respectively, in Example 1D.MS (ESI) m/e 773, 775 (M−H)⁻, (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ1.78(m, 4H), 1.91 (m, 2H), 2.51 (m, 2H), 2.66 (s, 6H), 2.71 (m, 4H), 3.00(m, 2H), 3.17 (s, 3H), 3.36 (m, 6H), 3.76 (s, 3H), 4.05 (m, 1H), 6.90(d, 1H), 7.00 (m, 2H), 7.18 (m, 1H), 7.22 (m, 3H), 7.31 (d, 2H), 7.39(m, 2H), 7.83 (dd, 1H), 7.90 (d, 2H), 8.15 (s, 1H), 8.48 (d, 1H).

EXAMPLE 4903-(2-methoxy-4′-((((4-(((1R)-4-(4-methylpiperazin-1-yl)-1-((phenylthio)methyl)butyl)amino)-3-nitrophenyl)sulfonyl)amino)carbonyl)-1,1′-biphenyl-4-yl)-N,N-dimethylpropanamideEXAMPLE 490Atert-butyl(1R)-4-(4-methylpiperazin-1-yl)-4-oxo-1-((phenylthio)methyl)butylcarbamate

The desired product was prepared by substituting Example 480B andn-methylpiperazine for Example 122E and dimethylamine, respectively, inExample 122F. MS (ESI) m/e 406, 408 (M−H)⁻, (M+H)⁺.

EXAMPLE 490B4-(((1R)-4-(4-methylpiperazin-1-yl)-1-((phenylthio)methyl)butyl)amino)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 490A forExample 122F in Example 122G, then substituting the product obtained forExample 133A in Example 133B. MS (ESI) m/e 492, 494 (M−H)⁻, (M+H)⁺.

EXAMPLE 490C3-(2-methoxy-4′-((((4-(((1R)-4-(4-methylpiperazin-1-yl)-1-(phenylthio)methyl)butyl)amino)-3-nitrophenyl)sulfonyl)amino)carbonyl)-1,1′-biphenyl-4-yl)-N,N-dimethylpropanamide

The desired product was prepared by substituting Example 482A andExample 490B for Example 1B and Example 1C, respectively, in Example 1D.¹H NMR (300 MHz, DMSO-d₆) δ1.78 (m, 4H), 2.52 (dd, 2H), 2.61 (m, 6H),2.72 (s, 3H), 2.83 (s, 3H), 2.85 (m, 2H), 2.96 (s, 3H), 3.01 (m, 4H),3.37 (m, 2H), 3.76 (s, 3H), 4.11 (m, 1H), 6.91 (d, 1H), 7.01 (s, 1H),7.09 (d, 1H), 7.15 (d, 1H), 7.20 (m, 3H), 7.30 (d, 2H), 7.46 (d, 2H),7.90 (dd, 1H), 7.93 (d, 2H), 8.21 (d, 1H), 8.52 (d, 1H).

EXAMPLE 491 tert-butyl4-(2-(4′-((((4-(((1R)-3-(dimethylamino)-1-((phenylthio)methyl)propyl)amino)-3-nitrophenyl)sulfonyl)amino)carbonyl)-2-methoxy-1,1′-biphenyl-4-yl)ethyl)piperazine-1-carboxylateEXAMPLE 491A 4-(2-hydroxyethyl)-2-methoxyphenol

The desired product was prepared by substituting homovanillyl alcoholfor Example 201E in Example 201F.

EXAMPLE 491B methyl4′-(2-hydroxyethyl)-2′-methoxy-1,1′-biphenyl-4-carboxylate

The desired product was prepared by substituting Example 491A forExample 5A in Example 5B.

EXAMPLE 491C methyl2′-methoxy-4′-(2-oxoethyl)-1,1′-biphenyl-4-carboxylate

A solution of Example 491B (2.47 g, 8.63 mmol) in dichloromethane (25mL) at room temperature was treated with Dess-Martin periodinane (4.03g, 9.49 mmol), stirred for 90 minutes, and concentrated. The concentratewas purified by flash column chromatography on silica gel with 1:1 ethylacetate/hexanes to provide the desired product.

EXAMPLE 491D tert-butyl4-(2-(2-methoxy-4′-(methoxycarbonyl)-1,1′-biphenyl-4-yl)ethyl)piperazine-1-carboxylate

A solution of Example 491C (400 mg, 1.41 mmol) and tert-butyl1-piperazinecarboxylate (289 mg, 1.55 mmol) in 1,2-dichloroethane (5 mL)at room temperature was treated with sodium triacetoxyborohydride (329mg, 1.55 mmol), and stirred for 16 hours. The solution was purified byflash column chromatography on silica gel with 90:10:0.25dichloromethane/methanol/concentrated ammonium hydroxide to provide thedesired product.

EXAMPLE 491E4′-(2-(4-(tert-butoxycarbonyl)piperazin-1-yl)ethyl)-2′-methoxy-1,1′-biphenyl-4-carboxylicacid

The desired product was prepared by substituting Example 491D forExample 1A in Example 1B.

EXAMPLE 491F tert-butyl4-(2-(4′-((((4-(((1R)-3-(dimethylamino)-1-((phenylthio)methyl)propyl)amino)-3-nitrophenyl)sulfonyl)amino)carbonyl)-2-methoxy-1,1′-biphenyl-4-yl)ethyl)piperazine-1-carboxylate

The desired product was prepared by substituting Example 491E andExample 122G for Example 1B and Example 1C, respectively, in Example 1D.MS (ESI) m/e 845, 847 (M−H)⁻, (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ1.39(s, 9H), 2.08 (m, 2H), 2.52 (s, 6H), 2.42 (m, 4H), 2.58 (m, 2H), 2.76(m, 6H), 3.06 (m, 2H), 3.33 (t, 2H), 3.73 (s, 3H), 4.09 (m, 1H), 6.88(d, 1H), 6.90 (d, 1H), 6.98 (s, 1H), 7.18 (dd, 2H), 7.26 (tt, 2H), 7.32(dt, 2H), 7.38 (d, 2H), 7.82 (dd, 1H), 7.88 (d, 2H), 8.23 (d, 1H), 8.48(d, 1H).

EXAMPLE 4924-(2-(4′-((((4-(((1R)-3-(dimethylamino)-1-((phenylthio)methyl)propyl)amino)-3-nitrophenyl)sulfonyl)amino)carbonyl)-2-methoxy-1,1′-biphenyl-4-yl)ethyl)piperazine-1-carboxamide

A solution of Example 499 (40 mg, 0.05 mmol) in DMF (0.5 mL) at roomtemperature was treated with trimethylsilyl isocyanate (7 mg, 0.06mmol), and stirred for 16 hours. The solution was purified by flashcolumn chromatography on silica gel with 80:20:0.5dichloromethane/methanol/concentrated ammonium hydroxide to provide thedesired product. MS (ESI) m/e 788, 790 (M−H)⁻, (M+H)⁺; ¹H NMR (300 MHz,DMSO-d₆) δ2.11 (m, 2H), 2.69 (s, 6H), 2.71 (m, 2H), 2.86 (m, 4H), 3.05(m, 2H), 3.08 (m, 4H), 3.16 (d, 2H), 3.34 (t, 2H), 3.75 (s, 3H), 4.09(m, 1H), 6.13 (s, 2H), 6.88 (d, 1H), 6.95 (d, 1H), 7.00 (s, 1H),7.15-7.33 (m, 6H), 7.40 (d, 2H), 7.83 (dd, 1H), 7.88 (d, 2H), 8.14 (d,1H), 8.48 (d, 1H).

EXAMPLE 4934-(((1R)-5-(dimethylamino)-1-((phenylthio)methyl)pentyl)amino)-N-(4-(4-hydroxy-4-phenylpiperidin-1-yl)benzoyl)-3-nitrobenzenesulfonamideEXAMPLE 493A tert-butyl 4-(4-hydroxy-4-phenylpiperidin-1-yl)benzoate

A solution of 4-hydroxy-4-phenyl piperidine (221 mg, 1.25 mmol) in DMSO(1 mL) was treated with tert-butyl-4-fluorobenzoate (196 mg, 1.00 mmol)and powdered potassium carbonate (173 mg, 1.25 mmol), stirred vigorouslyat 125° C. for 16 hours, cooled to room temperature, diluted withdiethyl ether, washed with brine, dried (MgSO₄), filtered, andconcentrated to provide the desired product. MS (DCI(+)) m/e 354 (M+H)⁺.

EXAMPLE 493B 4-(4-hydroxy-4-phenylpiperidin-1-yl)benzoic acid

A solution of Example 493A (0.32 g, 0.91 mmol) in TFA (2 mL) at roomtemperature was stirred for 1 hour, and concentrated. The concentratewas azeotropically distilled with toluene three times and dried toprovide the desired product. MS (ESI(+)) m/e 298 (M+H)⁺.

EXAMPLE 493C4-(((1R)-5-(dimethylamino)-1-((phenylthio)methyl)pentyl)amino)-N-(4-(4-hydroxy-4-phenylpiperidin-1-yl)benzoyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 124E andExample 493B for Example 1C and Example 1B, respectively, in Example 1D.MS(ESI(+)) m/e 732 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ8.45 (d, 1H), 8.15(d, 1H), 7.84 (dd, 1H), 7.75 (d, 2H), 7.45 (d, 2H), 7.30 (m, 4H), 7.20(m, 4H), 6.95 (d, 1H), 6.87 (d, 2H), 5.00 (s, 1H), 4.02 (m, 1H), 3.65(m, 2H), 3.18 (m, 2H), 2.90 (m, 2H), 2.67 (s, 6H), 2.00 (m, 2H)1.85-1.50 (m, 6H), 1.35 (m, 2H).

EXAMPLE 4944-(((1R)-5-(dimethylamino)-1-((phenylthio)methyl)pentyl)amino)-N-(4-(4-methoxy-4-methylpiperidin-1-yl)benzoyl)-3-nitrobenzenesulfonamideEXAMPLE 494A tert-butyl 4-hydroxy-4-methylpiperidine-1-carboxylate

A solution of 3M methyl magnesium bromide in diethyl ether (2.0 mL) indiethyl ether (3 mL) at 0° C. was treated with a solution of tert-butyl4-oxo-1-piperidinecarboxylate (1.0 g, 5.00 mmol) in diethyl ether (5mL), warmed to room temperature, stirred for 18 hours, treated withsaturated NH₄Cl, and extracted with diethyl ether. The combined extractswere washed with brine, dried (MgSO₄), filtered, and concentrated. Theconcentratet was purified by flash chromatography on silica gel with20%-50% ethyl acetate/heptane to provide the desired product. MS(DCI(+)) m/e 216 (M+H)⁺.

EXAMPLE 494B tert-butyl 4-methoxy-4-methylpiperidine-1-carboxylate

A suspension of 60% NaH in mineral oil (160 mg, 4 mmol) in THF (5 mL) atroom temperature was treated with a solution of Example 494A (430 mg,2.00 mmol) in THF (5 mL), heated to 55° C. for 2 hours, cooled to roomtemperature, treated with HMPA (2.5 mL) and methyl iodide (0.50 mL),heated to 55° C. for 16 hours, cooled to room temperature, quenched with10% aqueous citric acid, and extracted twice with diethyl ether. Thecombined extracts were washed sequentially with water, saturated NaHCO₃,and brine, dried (MgSO₄), filtered, and concentrated. The concentratewas purified by flash column chromatography on silica gel with 10%-20%ethyl acetate/heptane to provide the desired product.

EXAMPLE 494C 4-methoxy-4-methylpiperidine

A solution of Example 494B (115 mg, 0.5 mmol) in TFA (1 mL) at roomtemperature was stirred for 1.5 hours and concentrated. The product wasazeotropically distilled with toluene three times and concentrated toprovide the desired product as the trifluoroacetate salt.

EXAMPLE 494D tert-butyl 4-(4-methoxy-4-methylpiperidin-1-yl)benzoate

A solution of Example 494C (0.5 mmol) in DMSO (0.5 mL) at roomtemperature was treated with tert-butyl-4-fluorobenzoate (118 mg, 0.60mmol) and powdered potassium carbonate (207 mg, 1.5 mmol), heated to125° C. for 16 hours, and cooled to room temperature. The mixture wasdiluted with ethyl acetate, washed with brine, dried (MgSO₄), filtered,and concentrated. The concentrate was purified by flash columnchromatography on silica gel with 10%-30% ethyl acetate/hexanes toprovide the desired product. MS (DCI(+)) m/e 306 (M+H)⁺.

EXAMPLE 494E 4-(4-methoxy-4-methylpiperidin-1-yl)benzoic acid

The desired product was prepared by substituting Example 494D forExample 493A in Example 493B.

EXAMPLE 494F4-(((1R)-5-(dimethylamino)-1-((phenylthio)methyl)pentyl)amino)-N-(4-(4-methoxy-4-methylpiperidin-1-yl)benzoyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 494E andExample 124E for Example 1B and Example 1C, respectively, in Example 1D.MS(ESI(+)) m/e 684 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ8.45 (d, 1H), 8.15(d, 1H), 7.82 (dd, 1H), 7.73 (d, 2H), 7.30 (d, 2H), 7.25 (t, 2H), 7.15(m, 1H), 6.95 (d, 1H), 6.80 (d, 2H), 4.02 (m, 1H), 3.35 (m, 2H), 3.10(s, 3H), 3.05 (m, 2H), 2.90 (m, 2H), 2.68 (s, 6H), 1.75 (m, 4H), 1.55(m, 4H), 1.30 (m, 4H), 1.10 (s, 3H).

EXAMPLE 4954-(((1R)-5-(dimethylamino)-1-((phenylthio)methyl)pentyl)amino)-N-(4-(4-ethyl-4-hydroxypiperidin-1-yl)benzoyl)-3-nitrobenzenesulfonamideEXAMPLE 495A tert-butyl 4-ethyl-4-hydroxypiperidine-1-carboxylate

The desired product was prepared by substituting ethyl magnesium bromidefor methyl magnesium bromide in Example 494A.

EXAMPLE 495B 4-ethylpiperidin-4-ol

The desired product was prepared by substituting Example 495A forExample 492B in Example 492C.

EXAMPLE 495C tert-butyl 4-(4-ethyl-4-hydroxypiperidin-1-yl)benzoate

The desired product was prepared by substituting Example 495B forExample 494C in Example 494D.

EXAMPLE 495D 4-(4-ethyl-4-hydroxypiperidin-1-yl)benzoic acid

The desired product was prepared by substituting Example 495C forExample 493A in Example 493B.

EXAMPLE 495E4-(((1R)-5-(dimethylamino)-1-((phenylthio)methyl)pentyl)amino)-N-(4-(4-ethyl-4-hydroxypiperidin-1-yl)benzoyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 495D andExample 124E for Example 1B and Example 1C, respectively, in Example 1D.MS ESI(+)) m/e 684 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ11.95 (s, 1H),9.25 (s, 1H), 8.55 (d, 1H), 8.31 (d, 1H), 7.88 (dd, 1H), 7.72 (d, 2H),7.25-7.05 (m, 5H), 6.93 (d, 2H), 4.10 (m, 1H), 3.60 (m, 2H), 3.35 (m,2H), 3.20 (m, 2H), 2.95 (m, 2H), 2.70 (d, 6H), 1.75 (m, 2H), 1.55 (m,2H), 1.50-1.30 (m, 8H), 0.80 (t, 3H).

EXAMPLE 496N-(4-(4-benzyl-4-hydroxypiperidin-1-yl)benzoyl)-4-(((1R)-5-(dimethylamino)-1-((phenylthio)methyl)pentyl)amino)-3-nitrobenzenesulfonamideEXAMPLE 496A tert-butyl 4-(4-benzyl-4-hydroxypiperidin-1-yl)benzoate

The desired product was prepared by substituting 4-hydroxy-4-benzylpiperidine for 4-hydroxy-4-phenyl piperidine in Example 493A.

EXAMPLE 496B 4-(4-benzyl-4-hydroxypiperidin-1-yl)benzoic acid

The desired product was prepared by substituting Example 496A forExample 493A in Example 493B.

EXAMPLE 496CN-(4-(4-benzyl-4-hydroxypiperidin-1-yl)benzoyl)-4-(((1R)-5-(dimethylamino)-1-((phenylthio)methyl)pentyl)amino)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 124E andExample 496B for Example 1C and Example 1B, respectively, in Example 1D.MS (ESI(+)) m/e 746 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ8.45 (d, 1H),8.15 (d, 1H), 7.80 (dd, 1H), 7.70 (d, 2H), 7.35-7.15 (m, 10H), 6.95 (d,1H), 6.80 (d, 2H), 4.30 (s, 1H), 4.02 (s, 1H), 3.45 (m, 2H), 3.05 (m,2H), 2.90 (m, 2H), 2.70 (s, 2H), 2.65 (s, 6H), 1.75 (m, 2H), 1.55 (m,4H), 1.50-1.20 (m, 4H).

EXAMPLE 497N˜2˜-((4′-((((4-(((1R)-4-(dimethylamino)-1-((phenylthio)methyl)butyl)amino)-3-nitrophenyl)sulfonyl)amino)carbonyl)-2-methoxy-1,1′-biphenyl-4-yl)methyl)-N˜1˜,N˜1˜,N˜2˜-trimethylglycinamide EXAMPLE 497A methyl4′-(((2-(dimethylamino)-2-oxoethyl)(methyl)amino)methyl)-2′-methoxy-1,1′-biphenyl-4-carboxylate

The desired product was prepared by substituting Example 122I andsarcosine dimethylamide for Example 491C and tert-butyl1-piperazinecarboxylate, respectively, in Example 491D.

EXAMPLE 497B4′-(((2-(dimethylamino)-2-oxoethyl)(methyl)amino)methyl)-2′-methoxy-1,1′-biphenyl-4-carboxylicacid

The desired product was prepared by substituting Example 497A forExample 1A in Example 1B.

EXAMPLE 497CN˜2˜-((4′-((((4-(((1R)-4-(dimethylamino)-1-((phenylthio)methyl)butyl)amino)-3-nitrophenyl)sulfonyl)amino)carbonyl)-2-methoxy-1,1′-biphenyl-4-yl)methyl)-N˜1˜,N˜1˜,N˜2˜-trimethylglycinamide

The desired product was prepared by substituting Example 497B andExample 489A for Example 1B and Example 1C, respectively, in Example 1D.MS (ESI) m/e 775, 777 (M−H)⁻, (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ1.55(m, 4H), 1.75 (m, 2H), 2.20 (s, 3H), 2.32 (s, 6H), 2.45 (t, 2H), 2.81(s, 3H), 3.02 (s, 3H), 3.23 (s, 2H), 3.58 (s, 2H), 3.74 (s, 3H), 4.02(m, 1H), 6.95 (d, 2H), 7.04 (s, 1H), 7.18 (dt, 1H), 7.24 (m, 2H), 7.31(m, 2H), 7.40 (d, 2H), 7.83 (dd, 1H), 7.89 (d, 2H), 8.11 (d, 2H), 8.47(d, 1H).

EXAMPLE 498A methyl4′-(((2-(dimethylamino)-2-oxoethyl)(methyl)amino)ethyl)-2′-methoxy-1,1′-biphenyl-4-carboxylate

The desired product was prepared by substituting sarcosine dimethylamidefor tert-butyl 1-piperazincarboxylate in Example 491D.

EXAMPLE 498B4′-(((2-(dimethylamino)-2-oxoethyl)(methyl)amino)ethyl)-2′-methoxy-1,1′-biphenyl-4-carboxylicacid

The desired product was prepared by substituting Example 498A forExample 1A in Example 1B.

EXAMPLE 498CN˜2˜-(2-(4′-((((4-(((1R)-4-(dimethylamino)-1-((phenylthio)methyl)butyl)amino)-3-nitrophenyl)sulfonyl)amino)carbonyl)-2-methoxy-1,1′-biphenyl-4-yl)ethyl)-N˜1˜,N˜1˜,N˜2˜-trimethylglycinamide

The desired product was prepared by substituting Example 498B andExample 489A for Example 1B and Example 1C, respectively, in Example 1D.MS (ESI) m/e 789, 791 (M−H)⁻, (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ1.65(m, 4H), 1.75 (m, 2H), 2.35 (s, 3H), 2.57 (s, 6H), 2.78 (s, 3H), 2.81(m, 6H), 2.91 (s, 3H), 3.35 (s, 2H), 3.74 (s, 3H), 4.04 (m, 1H), 6.86(d, 1H), 6.96 (m, 2H), 7.18 (m, 2H), 7.25 (t, 2H), 7.32 (m, 2H), 7.38(d, 2H), 7.83 (dd, 1H), 7.88 (d, 2H), 8.14 (d, 1H), 8.47 (d, 1H).

EXAMPLE 4994-(((1R)-3-(dimethylamino)-1-((phenylthio)methyl)propyl)amino)-N-((2′-methoxy-4′-(2-piperazin-1-ylethyl)-1,1′-biphenyl-4-yl)carbonyl)-3-nitrobenzenesulfonamide

A solution of Example 491F (284 mg, 0.34 mmol) in 1,4-dioxane (1.5 mL)and 4M HCl (1.5 mL) at room temperature was stirred for 16 hours. Thesolution was purified by flash column chromatography on silica gel with80:20:0.5 dichloromethane/methanol/concentrated ammonium hydroxide toprovide the desired product. MS (ESI) m/e 745, 747 (M−H)⁻, (M+H)⁺; ¹HNMR (300 MHz, DMSO-d₆) δ2.11 (m, 2H), 2.62 (s, 6H), 2.67 (m, 4H), 2.77(m, 2H), 3.00 (m, 2H), 3.06 (m, 4H), 3.16 (d, 2H), 3.33 (t, 2H), 3.75(s, 3H), 4.09 (m, 1H), 6.88 (d, 1H), 6.95 (d, 1H), 6.98 (s, 1H),7.15-7.22 (m, 2H), 7.24-7.33 (m, 4H), 7.38 (d, 2H), 7.82 (dd, 1H), 7.88(d, 2H), 8.17 (d, 1H), 8.47 (d, 1H).

EXAMPLE 500 tert-butyl4-((4′-((((4-(((1R)-3-(dimethylamino)-1-((phenylthio)methyl)propyl)amino)-3-nitrophenyl)sulfonyl)amino)carbonyl)-2-methoxy-1,1′-biphenyl-4-yl)methyl)-3-oxopiperazine-1-carboxylateEXAMPLE 500A piperazin-2-one

A solution of ethylenediamine (66.40 g, 1106 mmol) in ethanol (300 mL)at room temperature was treated dropwise with a solution of ethylchloroacetate (20.00 g, 184 mmol) in ethanol (100 mL) over 3 hours,stirred for 2 hours, treated with sodium ethoxide (13.13 g, 193 mmol),and filtered. The filtrate was concentrated, dissolved in DMF (200 mL),stirred for 16 hours, heated to 65° C. for 72 hours, cooled to roomtemperature, and concentrated. The concentrate was purified by flashcolumn chromatography on silica gel with 80:20:0.5dichloromethane/methanol/concentrated ammonium hydroxide to provide thedesired product.

EXAMPLE 500B tert-butyl 3-oxopiperazine-1-carboxylate

A solution of Example 500A (500 mg, 4.99 mmol) in acetonitrile (25 mL)at room temperature was treated with BOC₂O (1198 mg, 5.49 mmol), stirredfor 3 hours, and concentrated. The concentrate was purified by flashcolumn chromatography on silica gel with 95:5 ethyl acetate/methanol toprovide the desired product.

EXAMPLE 500C methyl4′-(bromomethyl)-2′-methoxy-1,1′-biphenyl-4-carboxylate

A solution of Example 417A (1.50 g, 5.51 mmol) in DMF (18.0 mL) at 0° C.was treated with LiBr (526 mg, 6.06 mmol) and PBr₃ (1.64 g, 6.06 mmol),warmed to room temperature, and stirred for 30 minutes. The solution waspurified by flash column chromatography on silica gel with 3:7 ethylacetate/hexanes to provide the desired product.

EXAMPLE 500D tert-butyl4-((2-methoxy-4′-(methoxycarbonyl)-1,1′-biphenyl-4-yl)methyl)-3-oxopiperazine-1-carboxylate

A solution of Example 500B (328 mg, 1.64 mmol) in DMF (4 mL) at roomtemperature was treated with 15-crown-5 (361 mg, 1.64 mmol) and 60%sodium hydride in mineral oil (66 mg, 1.64 mmol). The mixture wastreated with a solution of Example 500C (500 mg, 1.49 mmol) in DMF (2mL), heated to 60° C. for 16 hours, cooled to room temperature, treatedwith water (20 mL), and extracted three times with ethyl acetate (50mL). The combined extracts were washed with brine (10 mL), dried(Na₂SO₄), filtered, and concentrated. The concentrate was purified byflash column chromatography on silica gel with 1:1 ethyl acetate/hexanesto provide the desired product.

EXAMPLE 500E4′-((4-(tert-butoxycarbonyl)-2-oxopiperazin-1-yl)methyl)-2′-methoxy-1,1′-biphenyl-4-carboxylicacid

The desired product was prepared by substituting Example 500D forExample 1A in Example 1B.

EXAMPLE 500F tert-butyl4-((4′-((((4-(((1R)-3-(dimethylamino)-1-((phenylthio)methyl)propyl)amino)-3-nitrophenyl)sulfonyl)amino)carbonyl)-2-methoxy-1,1′-biphenyl-4-yl)methyl)-3-oxopiperazine-1-carboxylate

The desired product was prepared by substituting Example 500E andExample 122G for Example 1B and Example 1C, respectively, in Example 1D.MS (ESI) m/e 845, 847 (M−H)⁻, (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ1.41(s, 9H), 2.01 (m, 2H), 2.33 (s, 6H), 2.65 (m, 2H), 3.27 (d, 2H), 3.32(t, 2H), 3.56 (t, 2H), 3.74 (s, 3H), 4.01 (s, 2H), 4.09 (m, 1H), 4.57(s, 2H), 6.88 (m, 2H), 6.98 (s, 1H), 7.18 (dt, 1H), 7.26 (m, 3H), 7.32(m, 2H), 7.39 (d, 2H), 7.81 (dd, 1H), 7.88 (d, 2H), 8.34 (d, 1H), 8.47(d, 1H).

EXAMPLE 5014-(((1R)-3-(dimethylamino)-1-((phenylthio)methyl)propyl)amino)-N-((2′-methoxy-4′-((2-oxopiperazin-1-yl)methyl)-1,1′-biphenyl-4-yl)carbonyl)-3-nitrobenzenesulfonamide

A solution of Example 500F (73 mg, 0.09 mmol) in dioxane (1 mL) and 4MHCl (1 mL) at room temperature was stirred for 16 hours, and purified byflash column chromatography on silica gel with 80:20:0.5dichloromethane/methanol/concentrated ammonium hydroxide to provide thedesired product. MS (ESI) m/e 745, 747 (M−H)⁻, (M+H)⁺; ¹H NMR (300 MHz,DMSO-d₆) δ2.07 (m, 2H), 2.54 (d, 6H), 2.74 (m, 1H), 3.04 (m, 2H), 3.17(d, 2H), 3.23 (t, 2H), 3.32 (t, 2H), 3.47 (s, 2H), 3.74 (s, 3H), 4.09(m, 1H), 4.54 (s, 2H), 6.89-6.99 (m, 3H), 7.17 (tt, 2H), 7.22-7.34 (m,4H), 7.39 (d, 2H), 7.81 (dd, 1H), 7.88 (dd, 2H), 8.21 (d, 1H), 8.47 (d,1H).

EXAMPLE 502N-(4-(4-(4-methoxybenzoyl)piperazin-1-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting 4-methoxybenzoylchloride for 2-methoxyethyl chloroformate in Example 325. MS (ESI(−))m/e 674 (M−H)⁻; ¹H NMR (500 MHz, DMSO-d₆) δ12.02 (s, 1H), 8.76 (t, 1H),8.61 (d, 1H), 7.92 (dd, 1H), 7.77 (d, 2H), 7.41 (d, 2H), 7.37 (d, 2H),7.26 (t, 2H), 7.15-7.20 (m, 2H), 6.99 (d, 2H), 6.95 (d, 2H), 3.80 (s,3H), 3.67 (q, 2H), 3.61 (br s, 4H), 3.39 (br s, 4H), 3.28 (t, 2H).

EXAMPLE 503N-(4-(4-((3-fluorophenyl)sulfonyl)piperazin-1-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting 3-fluorobenzenesulfonylchloride for 2-methoxyethyl chloroformate in Example 325. MS (ESI(−))m/e 698 (M−H)⁻; ¹H NMR (500 MHz, DMSO-d₆) δ12.04 (s, 1H), 8.77 (t, 1H),8.59 (d, 1H), 7.89 (dd, 1H), 7.69-7.75 (m, 3H), 7.58-7.63 (m, 3H), 7.36(d, 2H), 7.26 (t, 2H), 7.14-7.20 (m, 2H), 6.92 (d, 2H), 3.66 (q, 2H),3.40-3.44 (m, 4H), 3.28 (t, 2H), 3.01-3.05 (m, 4H).

EXAMPLE 504N-(4-(4-((4-fluorophenyl)sulfonyl)piperazin-1-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting 4-fluorobenzenesulfonylchloride for 2-methoxyethyl chloroformate in Example 325. MS (ESI(−))m/e 698 (M−H)⁻; ¹H NMR (500 MHz, DMSO-d₆) δ12.04 (s, 1H), 8.77 (t, 1H),8.59 (d, 1H), 7.90 (dd, 1H), 7.86-7.82 (m, 2H), 7.73 (d, 2H), 7.49 (t,2H), 7.36 (d, 2H), 7.26 (t, 2H), 7.20-7.14 (m, 2H), 6.91 (d, 2H), 3.66(q, 2H), 3.44-3.40 (m, 4H), 3.28 (t, 2H), 3.01-2.98 (m, 4H).

EXAMPLE 5053-nitro-4-((2-(phenylthio)ethyl)amino)-N-(4-(4-((4-propylphenyl)sulfonyl)piperazin-1-yl)benzoyl)benzenesulfonamide

The desired product was prepared by substituting 4-propylbenzenesulfonylchloride for 2-methoxyethyl chloroformate in Example 325. MS (ESI(−))m/e 722 (M−H)⁻; ¹H NMR (500 MHz, DMSO-d₆) δ12.01 (s, 1H), 8.75 (t, 1H),8.58 (d, 1H), 7.89 (dd, 1H), 7.22 (d, 2H), 7.66 (d, 2H), 7.46 (d, 2H),7.36 (d, 2H), 7.26 (t, 2H), 7.14-7.20 (m, 2H), 6.90 (d, 2H), 3.66 (q,2H), 3.42-3.39 (m, 4H), 3.28 (t, 2H), 2.99-2.95 (m, 4H), 2.64 (t, 2H),1.60 (hextet, 2H), 0.86 (t, 3H).

EXAMPLE 506N-(4-(8-azaspiro(4.5)dec-8-yl)benzoyl)-3-nitro-4-((4-((phenylthio)methyl)piperidin-4-yl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 472C andExample 257C for Example 1C and Example 1B, respectively, in Example 1D.The crude product was purified by reverse-phase chromatography using aC-18 column and 50% CH₃CN/water containing 0.01M HCl to provide thedesired product as the hydrochloride salt. MS (ESI) m/e 662, 664 (M−H)⁻,(M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ1,42 (m, 8H), 1.59 (m, 4H), 2.05 (m,2H), 3.02 (m, 2H), 3.21 (m, 2H), 3.35 (m, 4H), 3.63 (m, 4H), 6.86 (m,3H), 6.96 (d, 2H), 7.21 (d, 2H), 7.33 (d, 1H), 7.79 (m, 3H), 8.29 (d,1H), 8.46 (d, 1H), 9.02 (br s, 2H).

EXAMPLE 507(4R)-4-((4-(((4-(8-azaspiro(4.5)dec-8-yl)benzoyl)amino)sulfonyl)-2-nitrophenyl)amino)-N,N-dimethyl-5-(phenylthio)pentanamide

The desired product was prepared by substituting Example 480D andExample 257C for Example 1C and Example 1B, respectively, in Example 1D.MS (ESI) m/e 692, 694 (M−H)⁻, (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ1.41(m, 4H), 1.48 (m, 4H), 1.59 (m, 4H), 1.93 (m, 2H), 2.38 (m, 2H), 2.75(s, 3H), 2.83 (s, 3H), 3.19 (m, 4H), 3.32 (m, 3H), 4.04 (m, 1H), 6.80(d, 2H), 6.91 (d, 1H), 7.15 (dd, 1H), 7.22 (dd, 2H), 7.31 (d, 2H), 7.72(d, 2H), 7.79 (dd, 1H), 8.12 (d, 1H), 8.42 (d, 1H).

EXAMPLE 508N-(4-(8-azaspiro(4.5)dec-8-yl)benzoyl)-4-(((1R)-4-(dimethylamino)-1-((phenylthio)methyl)butyl)amino)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 489A andExample 257C for Example 1C and Example 1B, respectively, in Example 1D.MS (ESI) m/e 678 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ1.41 (m, 4H), 1.48(m, 4H), 1.59 (m, 4H), 1.85 (m, 2H), 2.41 (s, 6H), 2.62 (m, 2H), 2.66(m, 2H), 3.19 (M, 4H), 3.31 (ddd, 2H), 4.02 (m, 1H), 6.80 (d, 2H), 6.93(d, 1H), 7.16 (dd, 1H), 7.22 (dd, 2H), 7.31 (d, 2H), 7.73 (d, 2H), 7.81(dd, 1H), 8.12 (d, 1H), 8.46 (d, 1H).

EXAMPLE 5094-(((1R)-4-(dimethylamino)-1-((phenylthio)methyl)butyl)amino)-N-((2′-methoxy-4′-(3-morpholin-4-ylpropyl)-1,1′-biphenyl-4-yl)carbonyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 489A andExample 122O for Example 1C and Example 1B, respectively, in Example 1D.MS (ESI) m/e 774, 776 (M−H)⁻, (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ1.77(m, 4H), 2.05 (m, 2H), 2.68 (s, 6H), 2.96-3.05 (m, 9H), 3.37 (m, 4H),3.77 (s, 3H), 3.84 (m, 4H), 4.08 (m, 1H), 6.90 (d, 1H), 6.99 (s, 1H),7.03 (d, 1H), 7.16 (dd, 1H), 7.21 (s, 1H), 7.23 (dd, 2H), 7.30 (d, 2H),7.42 (d, 2H), 7.85 (dd, 2H), 7.91 (d, 2H), 8.15 (d, 1H), 8.50 (d, 1H).

EXAMPLE 510N-(4-(8-azaspiro(4.5)dec-8-yl)benzoyl)-4-(((1R)-3-(4-methylpiperazin-1-yl)-1-((phenylthio)methyl)propyl)amino)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 481A andExample 257C for Example 1C and Example 1B, respectively, in Example 1D.MS (ESI) m/e 719, 721 (M−H)⁻, (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ1.41(m, 4H), 1.48 (m, 4H), 1.59 (m, 4H), 1.72 (m, 4H), 1.82 (m, 2H), 2.41(s, 3H), 2.91 (m, 2H), 3.01 (m, 2H), 3.05 (m, 2H), 3.19 (m, 4H), 3.36(m, 2H), 4.09 (m, 1H), 6.80 (d, 2H), 6.95 (d, 1H), 7.17 (dd, 1H), 7.22(dd, 2H), 7.31 (d, 2H), 7.74 (d, 2H), 7.81 (dd, 1H), 8.23 (d, 1H), 8.46(d, 1H).

EXAMPLE 511N-((4′-(3-hydroxypropyl)-2′-methoxy-1,1′-biphenyl-4-yl)carbonyl)-4-(((1R)-3-(4-methylpiperazin-1-yl)-1-((phenylthio)methyl)propyl)amino)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 481A andExample 451B for Example 1C and Example 1B, respectively, in Example 1D.The product was dissolved in TFA (5 mL) and stirred at room temperaturefor 90 minutes, concentrated, dissolved in toluene, and concentratedagain to provide the desired product MS (ESI) m/e 746, 748 (M−H)⁻,(M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ1.77 (m, 4H), 2.63 (m, 2H), 2.66 (s,6H), 3.00 (m, 6H), 3.04 (m, 4H), 3.37 (m, 2H), 3.42 (m, 2H), 3.84 (m,4H), 4.15 (m, 2H), 6.85 (d, 1H), 6.93 (s, 1H), 7.03 (d, 1H), 7.16 (dd,1H), 7.21 (s, 1H), 7.23 (dd, 2H), 7.30 (d, 2H), 7.44 (d, 2H), 7.88 (dd,2H), 7.91 (d, 2H), 8.25 (d, 1H), 8.51 (d, 1H).

EXAMPLE 512N-((2′-methoxy-4′-(3-morpholin-4-ylpropyl)-1,1′-biphenyl-4-yl)carbonyl)-4-(((1R)-4-(4-methylpiperazin-1-yl)-1-((phenylthio)methyl)butyl)amino)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 490B andExample 122O for Example 1C and Example 1B, respectively, in Example 1D.MS (ESI) m/e 829, 831 (M−H)⁻, (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ1.59(m, 2H), 1.79 (m, 4H), 2.22 (dd, 2H), 2.29 (m, 4H), 2.34 (m, 2H), 2.52(m, 2H), 2.62 (m, 2H), 3.01 (m, 6H), 3.02 (s, 3H), 3.14 (m, 1H), 3.32(m, 2H), 3.59 (m, 4H), 3.76 (s, 3H), 4.00 (m, 1H), 6.85 (d, 1H), 6.93(s, 1H), 6.96 (d, 1H), 7.18 (dd, 1H), 7.19 (s, 1H), 7.23 (dd, 2H), 7.31(d, 2H), 7.40 (d, 2H), 7.85 (dd, 1H), 7.91 (d, 2H), 8.17 (d, 1H), 8.49(d, 1H).

EXAMPLE 513N-(4-(8-azaspiro(4.5)dec-8-yl)benzoyl)-4-(((1R)-4-(4-methylpiperazin-1-yl)-1-((phenylthio)methyl)butyl)amino)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 490B andExample 257C for Example 1C and Example 1B, respectively, in Example 1D.MS (ESI) m/e 733, 735 (M−H)⁻, (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ1.41(m, 4H), 1.48 (m, 4H), 1.59 (m, 4H), 1.72 (m, 4H), 1.82 (m, 2H), 2.33(s, 3H), 2.48 (m, 2H), 2.59 (s, 4H), 2.82 (m, 4H), 3.19 (m, 4H), 3.31(m, 2H), 4.00 (m, 1H), 6.80 (d, 2H), 6.95 (d, 1H), 7.17 (dd, 1H), 7.22(dd, 2H), 7.31 (d, 2H), 7.74 (d, 2H), 7.81 (dd, 1H), 8.15 (d, 1H), 8.43(d, 1H).

EXAMPLE 514N-((4′-(2-((2-(dimethylamino)ethyl)(methyl)amino)ethyl)-2′-methoxy-1,1′-biphenyl-4-yl)carbonyl)-4-(((1R)-3-(dimethylamino)-1-((phenylthio)methyl)propyl)amino)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 122G andExample 191C for Example 1C and Example 1B, respectively, in Example 1D.MS (ESI) m/e 747, 749 (M−H)⁻, (M+H)⁺; ¹NMR (300 MHz, DMSO-d₆) δ1.75 (m,4H), 2.20 (m, 2H), 2.66 (s, 6H), 2.70 (s, 6H), 2.96-3.04 (m, 8H), 3.36(m, 2H), 3.78 (s, 3H), 4.18 (m, 1H), 6.97 (d, 1H), 7.01 (s, 1H), 7.04(d, 1H), 7.18 (dd, 1H), 7.21 (s, 1H), 7.25 (dd, 2H), 7.31 (d, 2H), 7.43(d, 2H), 7.84 (dd, 1H), 7.91 (d, 2H), 8.15 (d, 1H), 8.49 (d, 1H).

EXAMPLE 5154-(((1R)-3-(dimethylamino)-1-((phenylthio)methyl)propyl)amino)-N-((2′-methoxy-4′-(2-(4-methylpiperazin-1-yl)ethyl)-1,1′-biphenyl-4-yl)carbonyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 122G andExample 242B for Example 1C and Example 1B, respectively, in Example 1D.MS (ESI) m/e 759, 761 (M−H)⁻, (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ2.20(m, 2H), 2.48 (s, 3H), 2.68 (s, 6H), 2.72 (m, 2H), 2.97-3.05 (m, 4H),3.14 (s, 2H), 3.17 (m, 2H), 3.36 (m, 6H), 3.76 (s, 3H), 4.18 (m, 1H),6.91 (d, 1H), 7.01 (s, 1H), 7.04 (d, 1H), 7.18 (dd, 1H), 7.21 (s, 1H),7.23 (dd, 2H), 7.31 (d, 2H), 7.41 (d, 2H), 7.83 (dd, 1H), 7.90 (d, 2H),8.14 (d, 1H), 8.49 (d, 1H).

EXAMPLE 5164-(((1R)-4-(dimethylamino)-1-((phenylthio)methyl)butyl)amino)-N-((2′-methoxy-4′-((4-methylpiperazin-1-yl)methyl)-1,1′-biphenyl-4-yl)carbonyl)-3-nitrobenzenesulfonamideEXAMPLE 516A methyl2′-methoxy-4′-((4-methylpiperazin-1-yl)methyl)-1,1′-biphenyl-4-carboxylate

The desired product was prepared by substituting Example 122I andN-methylpiperazine for Example 134A and dimethylamine, respectively, inExample 134B.

EXAMPLE 516B2′-methoxy-4′-((4-methylpiperazin-1-yl)methyl)-1,1′-biphenyl-4-carboxylicacid

The desired product was prepared by substituting Example 516A forExample 1A in Example 1B.

EXAMPLE 516C4-(((1R)-4-(dimethylamino)-1-((phenylthio)methyl)butyl)amino)-N-((2′-methoxy-4′-((4-methylpiperazin-1-yl)methyl)-1,1′-biphenyl-4-yl)carbonyl)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 489A andExample 516B for Example 1C and Example 1B, respectively, in Example 1D.MS (ESI) m/e 761 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ1.78 (m, 4H), 2.66(s, 9H), 2.70 (m, 2H), 3.00 (m, 2H), 3.14 (s, 2H), 3.35 (m, 6H), 3.61(m, 2H), 3.76 (s, 3H), 4.06 (m, 1H), 6.97 (d, 1H), 7.00 (s, 1H), 7.02(d, 1H), 7.16 (dd, 1H), 7.22 (s, 1H), 7.24 (dd, 2H), 7.31 (d, 2H), 7.41(d, 2H), 7.85 (dd, 1H), 7.90 (d, 2H), 8.14 (d, 1H), 8.49 (d, 1H).

EXAMPLE 517N-((2′-methoxy-4′-(2-(4-methylpiperazin-1-yl)ethyl)-1,1′-biphenyl-4-yl)carbonyl)-4-(((1R)-4-(4-methylpiperazin-1-yl)-1-((phenylthio)methyl)butyl)amino)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 490B andExample 242B for Example 1C and Example 1B, respectively, Example 1D. MS(ESI) m/e 828, 830 (M−H)⁻, (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ1.57 (m,2H), 1.77 (m, 2H), 2.46 (m, 2H), 2.50-2.63 (m, 10H), 2.82 (m, 4H), 2.91(m, 4H), 3.02 (m, 6H), 3.27 (m, 2H), 3.37 (m, 2H), 3.76 (s, 3H), 4.18(m, 1H), 6.90 (d, 1H), 6.96 (d, 1H), 7.01 (s, 1H), 7.18 (dd, 1H), 7.20(s, 1H), 7.22 (dd, 2H), 7.31 (d, 2H), 7.40 (d, 2H), 7.84 (dd, 1H), 7.91(d, 2H), 8.15 (d, 1H), 8.48 (d, 1H).

EXAMPLE 5183-nitro-N-(4-(1-oxa-9-azaspiro(5.5)undec-3-en-9-yl)benzoyl)-4-((2-(phenylthio)ethyl)amino)benzenesulfonamideEXAMPLE 518A tert-butyl 4-allyl-4-hydroxypiperidine-1-carboxylate

The desired product was prepared by substituting allyl magnesium bromidefor methyl magnesium bromide in Example 494A. MS (DCI(+)) m/e 242(M+H)⁺.

EXAMPLE 518B tert-butyl 4-allyl-4-(allyloxy)piperidine-1-carboxylate

The title compound was prepared by substituting Example 518A and allylbromide for Example 494A and methyl iodide, respectively, in Example494B. MS (DCI(+) m/e 282 (M+H)⁺.

EXAMPLE 518C tert-butyl 1-oxa-9-azaspiro(5.5)undec-3-ene-9-carboxylate

A solution of Example 518B (0.79 g, 2.81 mmol) in degassed benzene (100mL) at room temperature was treated with bis-tricyclohexylphosphinebenzylidene ruthenium (IV) dichloride (150 mg), stirred for 18 hours,and concentrated. The concentrate was purified by flash columnchromatography on silica gel with 10%-25% ethyl acetate/heptane toprovide the desired product. MS (DCI(+)) m/e 254 (M+H)⁺.

EXAMPLE 518D 1-oxa-9-azaspiro(5.5)undec-3-ene

The desired product was prepared by substituting Example 518C forExample 494B in Example 494C.

EXAMPLE 518E tert-butyl 4-(1-oxa-9-azaspiro(5.5)undec-3-en-9-yl)benzoate

The desired product was prepared by substituting Example 518D forExample 494C in Example 494D. MS (DCI(+)) m/e 330 (M+H)⁺.

EXAMPLE 518F 4-(1-oxa-9-azaspiro(5.5)undec-3-en-9-yl)benzoic acid

The desired product was prepared by substituting Example 518F forExample 493A in Example 493B. MS (DCI(+)) m/e 274 (M+H)⁺.

EXAMPLE 518G3-nitro-N-(4-(1-oxa-9-azaspiro(5.5)undec-3-en-9-yl)benzoyl)-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 518F andExample 77B for Example 1B and Example 1C, respectively, in Example 1D.MS (ESI(+)) m/e 609 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ11.95 (s, 1H),8.75 (t, 1H), 8.60 (d, 1H), 7.91 (dd, 1H), 7.73 (d, 2H), 7.37 (d, 2H),7.27 (t, 2H), 7.18 (m, 2H), 6.93 (d, 2H), 5.73 (s, 2H), 4.05 (s, 2H),3.65 (q, 2H), 3.59 (dt, 2H), 3.28 (m, 2H), 3.17 (m, 2H), 1.95 (m, 2H),1.75 (d, 2H), 1.52 (m, 2H).

EXAMPLE 519N-(4-(4-benzyl-4-hydroxypiperidin-1-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting Example 496B andExample 77B for Example 1B and Example 1C, respectively, in Example 1D.MS (ESI(+)) m/e 647 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ11.93 (s, 1H),8.75 (t, 1H), 8.60 (d, 1H), 7.91 (dd, 1H), 7.70 (d, 2H), 7.37 (d, 2H),7.22 (m, 9H), 6.90 (d, 2H), 4.40 (s, 1H), 3.65 (m, 4H), 3.28 (m, 2H),3.17 (m, 2H), 2.70 (s, 2H), 1.50 (m, 2H), 1.45 (m, 2H).

EXAMPLE 520N-(4-(2-azaspiro(4.4)non-2-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylthio)methyl)propyl)amino)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 120C andExample 122G for Example 1B and Example 1C, respectively, in Example 1D.MS (ESI(+)) m/e 652 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ11.90 (s, 1H),8.55 (d, 1H), 8.29 (d, 1H), 7.87 (dd, 1H), 7.73 (d, 2H), 7.24 (dd, 2H),7.08-7.18 (m, 4H), 6.51 (d, 2H), 4.20 (m, 1H), 3.35 (m, 4H), 3.15 (m,4H), 2.74 (s, 6H), 2.14 (m, 2H), 1.86 (t, 2H), 1.65 (m, 4H), 1.55 (m,4H).

EXAMPLE 521 ethyl4-methyl-1-(4-((((3-nitro-4-((2-(phenylthio)ethyl)amino)phenyl)sulfonyl)amino)carbonyl)phenyl)piperidine-4-carboxylate

The desired product was prepared by substituting Example 532F andExample 77B for Example 1B and Example 1C, respectively, in Example 1D.MS (ESI(+)) m/e 627 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ11.98 (s, 1H),8.77 (t, 1H), 8.60 (d, 1H), 7.91 (dd, 1H), 7.73 (d, 2H), 7.35 (m, 2H),7.26 (t, 2H), 7.18 (m, 2H), 6.93 (d, 2H), 4.13 (m, 2H), 3.66 (m, 4H),3.30 (m, 4H), 3.03 (m, 2H), 2.00 (m, 2H), 1.46 (m, 2H), 1.18 (t, 3H),1.17 (s, 3H).

EXAMPLE 522N-((5R)-5-((4-(((4-(8-azaspiro(4.5)dec-8-yl)benzoyl)amino)sulfonyl)-2-nitrophenyl)amino)-6-(phenylthio)hexyl)acetamide

The desired product was prepared by substituting acetic acid forN,N-dimethyglycine in Example 478. MS (ESI(+)) m/e 708, 706 (M+H)⁺,(M−H)⁻; ¹H NMR (500 MHz, DMSO-d₆) δ8.53 (d, 1H, 8.29 (d, 1H), 7.85 (dd,1H), 7.73 (d, 2H), 7.25-7.09 (m, 5H), 6.92 (d, 2H), 4.12 (m, 1H), 3.34(m, 4H), 2.97 (m, 2H), 1.73 (s, 3H), 1.60 (m, 4H), 1.52-1.34 (m, 12H).

EXAMPLE 523N-((5R)-5-((4-(((4-(8-azaspiro(4.5)dec-8-yl)benzoyl)amino)sulfonyl)-2-nitrophenyl)amino)-6-(phenylthio)hexyl)isonicotinamide

The desired product was prepared by substituting isonicotinic acid forN,N-dimethylglycine in Example 478. MS (ESI) m/e 771.3, 769.4 (M+H)⁺,(M−H)⁻; ¹H NMR (500 MHz, DMSO-d₆) δ8.69 (d, 2H), 8.52 (d, 1H), 8.30 (d,1H), 7.84 (dd, 1H), 7.73 (d, 2H), 7.70 (d, 2H), 7.09-7.25 (m, 5H), 6.92(d, 2H), 4.12 (m, 1H), 3.34 (m, 4H), 3.24 (m, 2H), 1.78 (m, 2H), 1.58(m, 4H), 1.52-1.34 (m, 12H).

EXAMPLE 524N¹-((5R)-5-((4-(((4-(8-azaspiro(4.5)dec-8-yl)benzoyl)amino)sulfonyl)-2-nitrophenyl)amino)-6-(phenylthio)hexyl)-N²-(2-carboxymethyl)-N²-methylglycinamide

The desired product was prepared by substituting methyliminodiaceticacid for N,N-dimethylglycine in Example 478. MS (ESI) m/e 795.3, 793.4(M+H)⁺, (M−H)⁻; ¹H NMR (500 MHz, DMSO-d₆) δ8.53(d, 1H), 8.29(d, 1H),8.12 (m, 1H), 7.85 (dd, 1H), 7.73 (d, 2H), 7.25-7.09 (m, 5H), 6.92 (d,2H), 4.12 (m, 1H), 3.34 (m, 4H), 3.17 (s, 3H), 3.01 (m, 2H), 2.58 (m,4H), 1.76 (m, 2H), 1.60 m, 4H), 1.52-1.34 (m, 12H).

EXAMPLE 525N˜1˜-((5R)-5-((4-(((4-(8-azaspiro(4.5)dec-8-yl)benzoyl)amino)sulfonyl)-2-nitrophenyl)amino)-6-(phenylthio)hexyl)glycinamide

The desired product was prepared by substitutingN-(t-butoxycarbonyl)glycine for N,N-dimethylglycine in Example 478. MS(ESI) m/e 723.3, 721.4 (M+H)⁺, (M−H)⁻; ¹H NMR (500 MHz, DMSO-d₆) δ8.53(d, 1H), 8.30 (d, 1H), 7.99 (m, 2H), 7.86 (dd, 1H), 7.74 (d, 2H),7.25-7.09 (m, 5H), 6.93 (d, 2H), 4.12 (m, 1H), 3.34 (m, 4H), 3.09 (m,2H), 1.75 (m, 2H), 1.60 (m, 4H), 1.52-1.34 (m, 12H).

EXAMPLE 526N-((5R)-5-((4-(((4-(8-azaspiro(4.5)dec-8-yl)benzoyl)amino)sulfonyl)-2-nitrophenyl)amino)-6-(phenylthio)hexyl)-1-methyl-L-prolinamide

The desired product was prepared by substituting N-methylproline forN,N-dimethylglycine in Example 478. MS (ESI) m/e 777.3, 775.4 (M+H)⁺,(M−H)⁻; ¹H NMR (500 MHz, DMSO-d₆) δ8.53 (d, 1H), 8.51 (m, 1H), 8.30 (d,1H), 7.86 (dd, 1H), 7.73 (d, 2H), 7.58 (m, 1H), 7.25-7.09 (m, 5H), 6.92(d, 2H), 4.12 (m, 1H), 3.89 (m, 1H), 3.51 (m, 1H), 3.34 (m, 4H), 3.10(m, 2H), 3.01 (m, 2H), 2.74 (s, 3H), 1.78 (m, 2H), 1.60 (m, 4H),1.52-1.34 (m, 14H).

EXAMPLE 527N-((5R)-5-((4-(((4-(8-azaspiro(4.5)dec-8-yl)benzoyl)amino)sulfonyl)-2-nitrophenyl)amino)-6-(phenylthio)hexyl)-1-methylcyclopropanecarboxamide

The desired product was prepared by substituting1-methylcyclopropanecarboxylic acid for N,N-dimethylglycine in Example478. MS (ESI) m/e 748.3, 746.4 (M+H)⁺, (M−H)⁻; ¹H NMR (500 MHz, DMSO-d₆)δ8.53 (d, 1H), 8.30 (d, 1H), 7.84 (dd, 1H), 7.73 (d, 2H), 7.39 (t, 1H),7.25-7.09 (m, 5H), 6.92 (d, 2H), 4.07 (m, 1H), 3.34 (m, 4H), 3.09 (m,2H), 1.74 (m, 2H), 1.60 (m, 4H), 1.52-1.34 (m, 12H), 1.16 (s, 3H), 0.85(q, 2H), 0.40 (q, 2H).

EXAMPLE 528N-((5R)-5-((4-(((4-(8-azaspiro(4.5)dec-8-yl)benzoyl)amino)sulfonyl)-2-nitrophenyl)amino)-6-(phenylthio)hexyl)-2-hydroxyacetamide

The desired product was prepared by substituting glycolic acid forN,N-dimethylglycine in Example 478. MS (ESI) m/e 724.3, 722.3 (M+H)⁺,(M−H)⁻; ¹H NMR (500 MHz, DMSO-d₆) δ8.53 (d, 1H), 8.30 (d, 1H), 7.84 (dd,1H), 7.73 (d, 2H), 7.65 (t, 1H), 7.25-7.09 (m, 5H), 6.92 (d, 2H), 4.09(m, 1H), 3.75 (s, 2H), 3.34 (m, 4H), 3.06 (m, 2H), 1.78 (m, 2H), 1.60(m, 4H), 1.52-1.34 (m, 12H).

EXAMPLE 529N-((5R)-5-((4-(((4-(8-azaspiro(4.5)dec-8-yl)benzoyl)amino)sulfonyl)-2-nitrophenyl)amino)-6-(phenylthio)hexyl)-2,2,2-trifluoroacetamide

The desired product was prepared by substituting trifluoroacetic acidfor N,N-dimethylglycine in Example 478. MS (ESI) m/e 762.2, 760.3(M+H)⁺, (M−H)⁻; ¹H NMR (500 MHz, DMSO-d₆) δ9.33 (t, 1H), 8.53 (d, 1H),8.30 (d, 1H), 7.84 (dd, 1H), 7.73 (d, 2H), 7.25-7.09 (m, 5H), 6.92 (d,2H), 4.09 (m, 1H), 3.34 (m, 4H), 3.13 (m, 2H), 1.75 (m, 2H), 1.60 (m,4H), 1.52-1.34 (m, 12H).

EXAMPLE 530N-(4-(4-benzyl-4-methoxypiperidin-1-yl)benzoyl)-4-(((1R)-5-(dimethylamino)-1-((phenylthio)methyl)pentyl)amino)-3-nitrobenzenesulfonamideEXAMPLE 530A tert-butyl 4-benzyl-4-hydroxypiperidine-1-carboxylate

A solution of 4-hydroxy-4-benzyl piperidine (0.66 g, 3.5 mmol) in 1MNaOH (7 mL, 7 mmol) and dioxane (5 mL) at 0° C. was treated with BOC₂O(0.76 g, 3.5 mmol), warmed to room temperature, stirred for 16 hours,adjusted to pH<7 with 10% citric acid, and extracted twice with ethylacetate. The combined extracts were washed with water and brine, dried(Na₂SO₄), filtered, and concentrated to provide the desired product.

EXAMPLE 530B tert-butyl 4-benzyl-4-methoxypiperidine-1-carboxylate

The desired product was prepared by substituting Example 530A forExample 494A in Example 494B. MS (DCI(+)) m/e 306 (M+H)⁺.

EXAMPLE 530C 4-benzyl-4-methoxypiperidine

The desired product was prepared by substituting Example 530B forExample 494B in Example 494C.

EXAMPLE 530D tert-butyl 4-(4-benzyl-4-methoxypiperidin-1-yl)benzoate

The desired product was prepared by substituting Example 530C forExample 494C in Example 494D.

EXAMPLE 530E 4-(4-benzyl-4-methoxypiperidin-1-yl)benzoic acid

The desired product was prepared by substituting Example 530D forExample 493A in Example 493B.

EXAMPLE 530FN-(4-(4-benzyl-4-methoxypiperidin-1-yl)benzoyl)-4-(((1R)-5-(dimethylamino)-1-((phenylthio)methyl)pentyl)amino)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 124E andExample 530E for Example 1C and Example 1B, respectively, in Example 1D.MS(ESI(+)) m/e 760 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ11.95 (s, 1H),9.20 (s, 1H), 8.55 (d, 1H), 8.31 (d, 1H), 7.88 (dd, 1H), 7.70 (d, 2H),7.30-7.05 (m, 11H), 6.90 (d, 2H), 4.10 (m, 1H), 3.65 (m, 2H), 3.35 (m,2H), 3.28 (s, 3H), 3.00 (m, 4H), 2.80 (s, 2H), 2.72 (s, 6H), 1.78 (m,2H), 1.68 (m, 2H), 1.60 (m, 2H), 1.50 (m, 2H), 1.30 (m, 2H).

EXAMPLE 531N-((4-benzylpiperidin-1-yl)carbonyl)-4-(((1R)-5-(dimethylamino)-1-((phenylthio)methyl)pentyl)amino)-3-nitrobenzenesulfonamide

The desired product was prepared by substituting Example 124E andExample 488B for Example 1C and Example 1B, respectively, in Example 1D.MS(ESI(+)) m/e 746 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ11.95 (s, 1H),9.20 (s, 1H), 8.55 (d, 1H), 8.31 (d, 1H), 7.88 (dd, 1H), 7.70 (d, 2H),7.30-7.05 (m, 11H), 6.90 (d, 2H), 4.10 (m, 1H), 3.65 (m, 2H), 3.15 (m,2H), 2.95 (m, 2H), 2.70 (m, 8H), 1.75 (m, 2H), 1.60-1.25 (m, 9H).

EXAMPLE 532N-(4-(4-(hydroxymethyl)-4-methylpiperidin-1-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamideEXAMPLE 532A 1-tert-butyl 4-ethyl piperidine-1,4-dicarboxylate

A solution of ethyl isonipecoate (2.5 g, 15.9 mmol) in dichloromethane(80 mL) at 0° C. was treated with (BOC)₂O (3.8 g, 17.3 mmol), warmed toroom temperature, stirred for 2 hours, diluted with water, and extractedwith dichloromethane. The combined extracts were washed sequentiallywith saturated sodium bicarbonate, 5% citric acid, and brine, dried(MgSO₄), filtered, and concentrated to provide the desired product. MS(ESI(+)) m/e 258 (M+H)⁺.

EXAMPLE 532B 1-tert-butyl 4-ethyl 4-methylpiperidine-1,4-dicarboxylate

A solution of Example 532A (2.1 g, 8.1 mmol) in THF (81 mL) at −78° C.was treated dropwise with 1.5M LDA in cyclohexane (6.0 mL, 8.9 mmol),stirred for 30 minutes, treated dropwise with methyl iodide (0.76 mmol),12.1 mmol), stirred for 2.5 hours, quenched with saturated NH₄Cl, andextracted with diethyl ether. The combined extracts were washed withbrine, dried (MgSO₄), filtered and concentrated to provide the desiredproduct. MS (DCI) m/e 272 (M+H)⁺.

EXAMPLE 532C ethyl 4-methylpiperidine-4-carboxylate

A solution of Example 532B (2.1 g, 8.0 mmol) in 4HCl in dioxane (10 mL)at room temperature was stirred for 3 hours and concentrated to providethe desired product. MS (DCI) m/e 171 (M+H)⁺.

EXAMPLE 532D benzyl 4-fluorobenzoate

A mixture of 4-fluorobenzoic acid (4.9 g, 35.3 mmol), benzyl bromide(3.8 mL, 31.7 mmol), and cesium carbonate (17.2 g, 53 mmol) in DMF (50mL) at room temperature was stirred for 24 hours, diluted with water,and extracted with diethyl ether. The combined extracts were washed withbrine, dried (MgSO₄), filtered, and concentrated to provide the desiredproduct. MS (DCI) m/e 248 (M+H)⁺.

EXAMPLE 532E ethyl1-(4-((benzyloxy)carbonyl)phenyl)-4-methylpiperidine-4-carboxylate

A mixture of Example 532C (2.2 g, 10.6 mmol), Example 532D (2.2 g, 9.9mmol), and potassium carbonate (2.9 g, 21.2 mmol) inN-methylpyrrolidinone (8.8 mL) was stirred at 150° C. for 24 hours,cooled to room temperature, diluted with water, and extracted withdichloromethane. The combined extracts were washed with water and brine,dried (MgSO₄), filtered, and concentrated. The concentrate was purifiedby flash column chromatogaphy on silica gel with 10% ethylacetate/hexanes to provide the desired product. MS (DCI) m/e 382 (M+H)⁺.

EXAMPLE 532F 4-(4-(ethoxycarbonyl)-4-methylpiperidin-1-yl)benzoic acid

A mixture of Example 532E (0.54 g, 1.4 mmol) in ethanol (6 mL) at roomtemperature was hydrogenated at 60 psi over 10% Pd/C (58 mg) for 1.5hours, filtered, and concentrated to provide the desired product. MS(DCI) m/e 292 (M+H)⁺.

EXAMPLE 532G ethyl4-methyl-1-(4-((((3-nitro-4-((2-(phenylthio)ethyl)amino)phenyl)sulfonyl)amino)carbonyl)phenyl)piperidine-4-carboxylate

The desired product was prepared by substituting Example 532F andExample 77B for Example 1B and Example 1C, respectively, in Example 1D.MS (ESI(+)) m/e 627 (M+H)⁺.

EXAMPLE 532H4-methyl-1-(4-((((3-nitro-4-((2-(phenylthio)ethyl)amino)phenyl)sulfonyl)amino)carbonyl)phenyl)piperidine-4-carboxylicacid

The desired product was prepared by substituting Example 532G forExample 119B in Example 119C. MS (ESI(+)) m/e 599.

EXAMPLE 532IN-(4-(4-(hydroxymethyl)-4-methylpiperidin-1-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

A solution of Example 532H (35 mg, 0.06 mmol), 4-methylmorpholine (0.007mL, 0.06 mmol), and DME (0.3 mL) at −15° C. was treated dropwise withisobutyl chloroformate (0.008 mL, 0.06 mmol), stirred for 15 minutes,and filtered. The filter cake was washed with DME and the filtrate andwashings were combined. The solution was cooled to −15° C., treatedsequentially with NaBH₄ (3.5 mg, 0.09 mmol) water (0.03 mL), andadditional water (50 mL), and extracted with dichloromethane. Thecombined extracts were washed with brine, dried (MgSO₄), filtered, andconcentrated. The concentrate was purifed by flash column chromatographyon silica gel with 1-2% methanol/dichloromethane to provide the desiredproduct. MS (ESI(−))) m/e 583 (M−H)⁻; ¹H NMR (500 MHz, DMSO-d₆) δ11.92(s, 1H), 8.75 (t, 1H), 8.58 (d, 1H), 7.90 (dd, 1H), 7.72 (d, 2H), 7.38(d, 2H), 7.27 (t, 2H), 7.15 (m, 2H), 6.90 (d, 2H), 4.53 (t, 1H), 3.66(m, 2H), 3.50 (m, 2H), 3.30 (m, 2H), 3.16 (m, 4H), 1.50 (m, 2H), 1.25(m, 2H), 0.91 (s, 3H).

EXAMPLE 533N-(4-(4-(2-naphthylsulfonyl)piperazin-1-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide

The desired product was prepared by substituting 2-napthalenesulfonylchloride for 2-methoxyethyl chloroformate in Example 325. MS (ESI(−))m/e 730 (M−H)⁻; ¹H NMR (500 MHz, DMSO-d₆) δ12.02 (s, 1H), 8.74 (t, 1H),8.57 (d, 1H), 8.46 (d, 1H), 8.21 (d, 1H), 8.16 (d, 1H), 8.06 (d, 1H),7.88 (dd, 1H), 7.77 (dd, 1H), 7.76-7.66 (m, 4H), 7.37-7.32 (m, 2H), 7.25(t, 2H), 7.19-7.14 (m, 2H), 6.89 (d, 2H), 3.65 (q, 2H), 3.42 (t, 4H),3.26 (t, 2H), 3.07 (t, 4H).

EXAMPLE 5344-(((1R)-5-((amino(imino)methyl)amino)-1-((phenylthio)methyl)pentyl)amino)-N-(4-(8-azaspiro(4.5)dec-8-yl)benzoyl)-3-nitrobenzenesulfonamide

A solution of Example 287 (30 mg, 0.05 mmol), aminoiminosulfonic acid (7mg, 0.055 mmol), diisopropylethylamine (0.02 Ml), and DMF (0.3 mL) atroom temperature was stirred for 24 hours and concentrated. Theconcentrate was purified by reverse phase chromatography with 0-90%methanol/0.1% aqueous TFA to provide the desired product. MS (ESI(+))m/e 708 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ12.02 (s, 1H), 8.53 (d, 1H),8.32 (d, 1H), 7.86 (dd, 1H), 7.73 (d, 2H), 7.39 (t, 1H), 7.25-7.10 (m,6H), 6.93 (d, 2H), 4.12 (m, 1H), 3.35 (m, 6H), 3.05 (m, 2H), 1.75 (m,2H), 1.59 (m, 4H), 1.42 (m, 8H).

It will be evident to one skilled in the art that the present inventionis not limited to the forgoing illustrative examples, and that it can beembodied in other specific forms without departing from the essentialattributes thereof. It is therefore desired that the examples beconsidered in all respects as illustrative and not restrictive,reference being made to the appended claims, rather than to theforegoing examples, and all changes which come within the meaning andrange of equivalency of the claims and therefore intended to be embracedtherein.

What is claimed is:
 1. A compound of formula (I):

or a therapeutically acceptable salt thereof, wherein R¹ is selected from the group consisting of alkyl, haloalkyl, nitro, and —NR⁵R⁶; R², and R³ are independently selected from the group consisting of hydrogen, alkenyl, alkoxy, alkyl, alkylsulfanyl, alkynyl, aryl, arylalkoxy, aryloxy, aryloxyalkoxy, arylsulfanyl, arylsulfanylalkoxy, carbonyloxy, cycloalkylalkoxy, cycloalkyloxy, halo, halolkoxy, haloalkyl, hydroxy, nitro, and —NR⁵R⁶; wherein the aryl and the aryl part of the arylalkoxy, the aryloxy, the aryloxyalkoxy, the arylsulfanyl, and arylsulfanylalkoxy can be optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of alkanoyl, alkenyl, alkoxy, alkoxyalkanoyl, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkynyl, carbonyloxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, —NR^(a)R^(b), oxo, and —C(NH)NH₂; and wherein the cycloalkyl part of the cycloalkylalkoxy and the cycloalkyloxy can be optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of alkoxy, alkoxycarbonyl, alkyl, NH₂CH₂—, arylalkoxy, aryloxy, arylsulfanyl, halo, haloalkoxy, haloalkyl, and hydroxy, wherein the aryl part of the arylalkoxy, the aryloxy, and the arylsulfanyl can be further optionally substituted with one, two, or three substituents independently selected from the group consisting of alkoxy, alkyl, halo, haloalkoxy, haloalkyl, and hydroxy; R⁵ and R⁶ are independently selected from the group consisting of hydrogen, alkenyl, alkoxyalkyl, alkoxycarbonylalkyl, alkyl, alkylsulfanylalkyl, alkylsulfonylalkyl, aryl, arylalkyl, arylalkylsulfanylalkyl, aryloxyalkyl, arylsulfanylalkyl, arylsulfinylalkyl, arylsulfonylalkyl, carboxyalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkylcarbonyl, (heterocycle)sulfanylalkyl, hydroxyalkyl, a nitrogen protecting group, and —N═CR⁷R⁸; R⁷ and R⁸ are alkyl, or R⁷ and R⁸, together with the carbon atom to which they are attached, form an aryl group which an be optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of alkanoyl, alkenyl, alkoxy, alkoxyalkanoyl, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkynyl, carbonyloxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, —NR^(a)R^(b), oxo, and —C(NH)NH₂; R¹⁵ is selected from the group consisting of hydrogen, alkyl, and halo; a is 0-5; each R²⁰ is independently selected from the group consisting of alkanoyl, alkanoylalkyl, alkenyl, alkoxy, alkoxyalkoxycarbonyl, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylsulfanylalkyl, alkynyl, aryl, arylalkoxyalkanoyl, arylalkoxycarbonyl, arylalkyl, arylalkylsulfonyl, arylcarbonyl, aryloxy, arylsulfanyl, arylsulfanylalkyl, arylsulfonyl, carbonyloxy, carboxy, cyano, cyanoalkyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkylcarbonyl, formyl, formylalkyl, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, —NR^(a)R^(b), oxo, spirocycle, and —C(NH)NH₂; wherein the aryl, the aryl part of the arylalkoxyalkanoyl, the arylalkoxycarbonyl, the arylalkyl, the arylalkylsulfonyl, the arylcarbonyl, the aryloxy, the arylsulfanyl, the arylsulfanylalkyl, and the arylsulfonyl can be optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of alkanoyl, alkenyl, alkoxy, alkoxyalkanoyl, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkynyl, carbonyloxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, —NR^(a)R^(b), oxo, and —C(NH)NH₂; and wherein the cycloalkyl part of the cycloalkylalkoxy and the cycloalkyloxy can be optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of alkoxy, alkoxycarbonyl, alkyl, NH₂CH₂—, arylalkoxy, aryloxy, arylsulfanyl, halo, haloalkoxy, haloalkyl, and hydroxy, wherein the aryl part of the arylalkoxy, the aryloxy, and the arylsulfanyl can be further optionally substituted with one, two, or three substituents independently selected from the group consisting of alkoxy, alkyl, halo, haloalkoxy, haloalkyl, and hydroxy; R^(a) and R^(b) are independently selected from the group consisting of hydrogen, alkanoyl, alkenyl, alkoxyalkyl, alkoxyalkoxyalkyl, alkoxycarbonyl, alkyl, unsubstituted aryl, unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted (cycloalkyl)alkyl, unsubstituted cycloalkylcarbonyl, haloalkanoyl, haloalkyl, hydroxyalkyl, and —CH(NH)NH₂.
 2. The compound of claim 1 wherein R² is NR⁵R⁶.
 3. The compound of claim 2 wherein one of R⁵ and R⁶ is hydrogen and the other is selected from the group consisting of arylsulfanylalkyl, arylsulfinylalkyl, and (cycloalkyl)alkyl.
 4. The compound of claim 3 wherein R²⁰ is spirocycle.
 5. The compound of claim 4 selected from the group consisting of N-(4-(8-azaspiro(4.5)dec-8-yl)benzoyl)-4-(((1R)-5-(dimethylamino)-1-((phenylthio)methyl)pentyl)amino)-3-nitrobenzenesulfonamide; N-(4-(8-azaspiro(4.5)dec-8-yl)benzoyl)-4-(((1R)-2-(dimethylamino)-1-((phenylthio)methyl)ethyl)amino)-3-nitrobenzenesulfonamide; N-((5R)-5-((4-(((4-(8-azaspiro(4.5)dec-8-yl)benzoyl)amino)sulfonyl)-2-nitrophenyl)amino)-6-(phenylthio)hexyl)-1H-imidazole-1-carboxamide; N-(4-(8-azaspiro(4.5)dec-8-yl)benzoyl)-4-(((1R)-2-morpholin-4-yl-1-((phenylthio)methyl)ethyl)amino)-3-nitrobenzenesulfonamide; N-(4-(8-azaspiro(4.5)dec-8-yl)benzoyl)-4-(((1R)-2-(4-methylpiperazin-1-yl)-1-((phenylthio)methyl)ethyl)amino)-3-nitrobenzenesulfonamide; 4-(((1R)-5-amino-1-((phenylthio)methyl)pentyl)amino)-N-(4-(6-azaspiro(2.5)oct-6-yl)benzoyl)-3-nitrobenzenesulfonamide; 4-(((4-(aminomethyl)bicyclo(2.2.2)oct-1-yl)methyl)amino)-N-(4-(8-azaspiro(4.5)dec-8-yl)benzoyl)-3-nitrobenzenesulfonamide; tert-butyl(5R)-5-((4-(((4-(6-azaspiro(2.5)oct-6-yl)benzoyl)amino)sulfonyl)-2-nitrophenyl)amino)-6-(phenylthio)hexylcarbamate; N-(4-(8-azaspiro(4.5)dec-8-yl)benzoyl)-4-((2,2-difluoro-2-(phenylthio)ethyl)amino) -3-nitrobenzenesulfonamide; N-(4-(8-azaspiro(4.5)dec-8-yl)benzoyl)-4-(((1R)-2-((2-(dimethylamino)ethyl)(methyl)amino)-1-((phenylthio)methyl)ethyl)amino)-3-nitrobenzenesulfonamide; N-(4-(8-azaspiro(4.5)dec-8-yl)benzoyl)-4-((3-(dimethylamino)-2-(phenylthio)propyl)amino)-3-nitrobenzenesulfonamide; tert-butyl(5R)-5-((4-(((4-(8-azaspiro(4.5)dec-8-yl)benzoyl)amino)sulfonyl)-2-nitrophenyl)amino)-6-(phenylthio)hexylcarbamate; N-(4-(8-azaspiro(4.5)dec-8-yl)benzoyl)-4-((2-methyl-2-(phenylthio)propyl)amino)-3-nitrobenzenesulfonamide; N-(4-(8-azaspiro(4.5)dec-8-yl)benzoyl)-4-((1,1-dimethyl-2-(phenylthio)ethyl)amino) -3-nitrobenzenesulfonamide; N-(4-(8-azaspiro(4.5)dec-8-yl)benzoyl)-4-(((1R)-2-hydroxy-1-((phenylthio)methyl)ethyl)amino)-3-nitrobenzenesulfonamide; 4-(((1R)-5-amino-1-((phenylthio)methyl)pentyl)amino)-N-(4-(8-azaspiro(4.5)dec-8-yl)benzoyl)-3-nitrobenzenesulfonamide; N-(4-(8-azaspiro(4.5)dec-8-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide; 4-(((1R)-5-((aminocarbonyl)amino)-1-((phenylthio)methyl)pentyl)amino)-N-(4-(8-azaspiro(4.5)dec-8-yl)benzoyl)-3-nitrobenzenesulfonamide; N-(4-(8-azaspiro(4.5)dec-8-yl)benzoyl)-4-(((1R)-5-(dimethylamino)-1-((phenylsulflnyl)methyl)pentyl)amino)-3-nitrobenzenesulfonamide; N˜1˜-((5R)-5-((4-(((4-(8-azaspiro(4.5)dec-8-yl)benzoyl)amino)sulfonyl)-2-nitrophenyl)amino)-6-(phenylthio)hexyl)-N˜2˜,N˜2˜-dimethylglycinamide; N-((5R)-5-((4-(((4-(8-azaspiro(4.5)dec-8-yl)benzoyl)amino)sulfonyl)-2-nitrophenyl)amino)-6-(phenylthio)hexyl)cyclopropanecarboxamide; (4R)-4-((4-(((4-(8-azaspiro(4.5)dec-8-yl)benzoyl)amino)sulfonyl)-2-nitrophenyl)amino)-N,N-dimethyl-5-(phenylthio)pentanamide; N-(4-(8-azaspiro(4.5)dec-8-yl)benzoyl)-4-(((1R)-4-(dimethylamino)-1-((phenylthio)methyl)butyl)amino)-3-nitrobenzenesulfonamide; N-(4-(8-azaspiro(4.5)dec-8-yl)benzoyl)-4-(((1R)-3-(4-methylpiperazin-1-yl)-1-((phenylthio)methyl)propyl)amino)-3-nitrobenzenesulfonamide; N-(4-(8-azaspiro(4.5)dec-8-yl)benzoyl)-4-(((1R)-4-(4-methylpiperazin-1-yl)-1-((phenylthio)methyl)butyl)amino)-3-nitrobenzenesulfonamide; N-((5R)-5-((4-(((4-(8-azaspiro(4.5)dec-8-yl)benzoyl)amino)sulfonyl)-2-nitrophenyl)amino)-6-(phenylthio)hexyl)acetamide; N-((5R)-5-((4-(((4-(8-azaspiro(4.5)dec-8-yl)benzoyl)amino)sulfonyl)-2-nitrophenyl)amino)-6-(phenylthio)hexyl)isonicotinamide; N¹-((5R)-5-((4-(((4-(8-azaspiro(4.5)dec-8-yl)benzoyl)amino)sulfonyl)-2-nitrophenyl)amino)-6-(phenylthio)hexyl)-N²-(2-carboxymethyl)-N²-methylglycinamide; N˜1˜-((5R)-5-((4-(((4-(8-azaspiro(4.5)dec-8-yl)benzoyl)amino)sulfonyl)-2-nitrophenyl)amino)-6-(phenylthio)hexyl)glycinamide; N-((5R)-5-((4-(((4-(8-azaspiro(4.5)dec-8-yl)benzoyl)amino)sulfonyl)-2-nitrophenyl)amino)-6-(phenylthio)hexyl)-1-methyl-L-prolinamide; N-((5R)-5-((4-(((4-(8-azaspiro(4.5)dec-8-yl)benzoyl)amino)sulfonyl)-2-nitrophenyl)amino)-6-(phenylthio)hexyl)-1-methylcyclopropanecarboxamide; N-((5R)-5-((4-(((4-(8-azaspiro(4.5)dec-8-yl)benzoyl)amino)sulfonyl)-2-nitrophenyl)amino)-6-(phenylthio)hexyl)-2-hydroxyacetamide; N-((5R)-5-((4-(((4-(8-azaspiro(4.5)dec-8-yl)benzoyl)amino)sulfonyl)-2-nitrophenyl)amino)-6-(phenylthio)hexyl)-2,2,2-trifluoroacetamide; and 4-(((1R)-5-((amino(imino)methyl)amino)-1-((phenylthio)methyl)pentyl)amino)-N-(4(8-azaspiro(4.5)dec-8-yl)benzoyl)-3-nitrobenzenesulfonamide.
 6. The compound of claim 3 wherein R²⁰ is selected from the group consisting of alkoxy, alkoxycarbonyl, alkyl, aryl, arylalkyl, formylalkyl, hydroxy, and hydroxyalkyl.
 7. The compound of claim 6 selected from the group consisting of N-(4-(4,4-dimethylpiperidin-1-yl)benzoyl)-4-(((1R)-3-morpholin-4-yl-1-((phenylthio)methyl)propyl)amino)-3-nitrobenzenesulfonamide; 4-(((1R)-3-(dimethylamino)-1-((phenylthio)methyl)propyl)amino)-N-(4-(4,4-dimethylpiperidin-1-yl)benzoyl)-3-nitrobenzenesulfonamide; 4-(((1R)-5-amino-1-((phenylthio)methyl)pentyl)amino)-N-(4-(4-ethyl-4-methylpiperidin-1-yl)benzoyl)-3-nitrobenzenesulfonamide; 4-(((1R)-5-(dimethylamino)-1-((phenylthio)methyl)pentyl)amino)-N-(4-(4,4-dimethylpiperidin-1-yl)benzoyl)-3-nitrobenzenesulfonamide; tert-butyl(5R)-5-((4-(((4-(4-ethyl-4-methylpiperidin-1-yl)benzoyl)amino)sulfonyl)-2-nitrophenyl)amino)-6-(phenylthio)hexylcarbamate; 3-nitro-N-(4-(4-(3-oxopropyl)piperidin-1-yl)benzoyl)-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide; N-(4-(4-(3-hydroxypropyl)piperidin-1-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide; N-(4-(3,3-dimethylpiperidin-1-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide; N-(4-(4-ethyl-4-methylpiperidin-1-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide; tert-butyl(5R)-5-((4-(((4-(4,4-dimethylpiperidin-1-yl)benzoyl)amino)sulfonyl)-2-nitrophenyl)amino)-6-(phenylthio)hexylcarbamate; 4-(((1R)-5-amino-1-((phenylthio)methyl)pentyl)amino)-N-(4-(4,4-dimethylpiperidin -1-yl)benzoyl)-3-nitrobenzenesulfonamide; 4-((1,1-dimethyl-2-(phenylthio)ethyl)amino)-N-(4-(4,4-dimethylpiperidin-1-yl)benzoyl)-3-nitrobenzenesulfonamide; N-(4-(4,4-dimethylpiperidin-1-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide; 4-(((1R)-3-(dimethylamino)-1-((phenylthio)methyl)propyl)amino)-N-(4-(4-ethyl-4-methylpiperidin-1-yl)benzoyl)-3-nitrobenzenesulfonamide; N-(4-(4-ethyl-4-methoxypiperidin-1-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide; N-(4-(4-benzylpiperidin-1-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide; 4-(((1R)-5-(dimethylamino)-1-((phenylthio)methyl)pentyl)amino)-N-(4-(4-hydroxy -4-phenylpiperidin-1-yl)benzoyl)-3-nitrobenzenesulfonamide; 4-(((1R)-5-(dimethylamino)-1-((phenylthio)methyl)pentyl)amino)-N-(4-(4-methoxy -4-methylpiperidin-1-yl)benzoyl)-3-nitrobenzenesulfonamide; 4-(((1R)-5-(dimethylamino)-1-((phenylthio)methyl)pentyl)amino)-N-(4-(4-ethyl-4-hydroxypiperidin-1-yl)benzoyl)-3-nitrobenzenesulfonamide; N-(4-(4-benzyl-4-hydroxypiperidin-1-yl)benzoyl)-4-(((1R)-5-(dimethylamino)-1-((phenylthio)methyl)pentyl)amino)-3-nitrobenzenesulfonamide; N-(4-(4-benzyl-4-hydroxypiperidin-1-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide; ethyl 4-methyl-1-(4-((((3-nitro-4-((2-(phenylthio)ethyl)amino)phenyl)sulfonyl)amino)carbonyl)phenyl)piperidine-4-carboxylate; N-(4-(4-benzyl-4-methoxypiperidin-1-yl)benzoyl)-4-(((1R)-5-(dimethylamino)-1-((phenylthio)methyl)pentyl)amino)-3-nitrobenzenesulfonamide; N-((4-benzylpiperidin-1-yl)carbonyl)-4-(((1R)-5-(dimethylamino)-1-((phenylthio)methyl)pentyl)amino)-3-nitrobenzenesulfonamide; and N-(4-(4-(hydroxymethyl)-4-methylpiperidin-1-yl)benzoyl)-3-nitro-4-((2-(phenylthio)ethyl)amino)benzenesulfonamide.
 8. The compound which is 4-(((1R)-3-(dimethylamino)-1-((phenylthio)methyl)propyl)amino)-N-(4-(4,4-dimethylpiperidin-1-yl)benzoyl)-3-nitrobenzenesulfonamide.
 9. A pharmaceutical composition comprising a compound of claim 1 or a therapeutically acceptable salt thereof, in combination with a therapeutically acceptable carrier. 